JP5137586B2 - Novel benzimidazole derivative and pharmaceutical composition containing the same - Google Patents

Description

  The present invention relates to a novel benzimidazole derivative, and more specifically, functions as an antagonist of vanilloid receptor (capsaicin receptor; Transient Receptor Potential Channel, Vanilloid subfamily member 1; TRPV-1; Vanilloid receptor-1; VR-1). The present invention relates to a novel benzimidazole derivative. The present invention also relates to a method for producing the benzimidazole derivative, its use and a pharmaceutical composition comprising the benzimidazole derivative as an active ingredient.

  The vanilloid receptor is a receptor for capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), a spicy component of chili pepper, and its existence has been presumed for some time. In 1997, the receptor was cloned and named vanilloid receptor subtype 1 (hereinafter referred to as VR-1) by Caterina et al. (Caterina et al., Nature, 1997, 389, 816). VR-1 is distributed in thin unmyelinated nerves (C-fiber) and thin myelinated nerves (A-fiber) in the human body, activated by external or internal stimulation, and cations such as calcium and sodium. It is known as an ion channel that plays a role in reducing pain stimulation by strongly injecting into the nerve fiber terminal. External stimuli that activate VR-1 have been reported to include not only vanilloid compounds but also thermal stimuli and harmful stimuli due to acids (Tominaga et al., Neuron, 1998, 21, 531), Internal stimuli include leukotriene metabolites such as 12-hydroperoxyeicosatetraenoic acid (12-HPTEE) (Hwang at al., PNAS, 2000, 97, 3655) and arachidonic acid derivatives such as anandamide (Premkumar et al ., Nature, 2000, 408, 985).

  Based on such physiological action, VR1 has been attracting attention as an integrated regulator responsible for functions important for transmitting various external noxious stimuli into nerve cells in vivo. In fact, a knockout mouse from which the VR1 gene has been removed has recently been produced (Caterina et al., Science, 2000, 288, 306). For stimuli, thermal hyperalgesia, etc., the results showed that the pain response was reduced by plating, indicating the importance of VR1 for noxious stimuli.

  In vivo, VR1 is abundantly expressed in primary sensory neurons (Caterina et al., Nature, 1997, 389, 816), and sensory nerves such as skin, skeleton, bladder, gastrointestinal tract, lungs, etc. It plays an essential role in regulating the functions of internal organs of the human body. In addition, VR1 is expressed in the central nervous system, kidney, stomach, T-cell (Nozawa et al., Neuroscience Letter, 2001, 309, 33; Yiangou et al., Lancet (North America Edition), 2001, 357, 1338; Birder et al., PNAS, 2001, 98, 13396), and is presumed to play an important role in cell division or cell signal regulation, distributed in other nerve cells or throughout the body.

  In this regard, currently, indications based on the modulation of VR1 activity include pain, acute pain, chronic pain, neuropathic pain, postoperative pain, migraine, joint pain, neuropathy, nerve damage, diabetic Neuropathy, neuropathic disease, neurodermatitis, stroke, bladder hypersensitivity, irritable enteropathy group, respiratory disease such as asthma, chronic obstructive pulmonary disease, irritation of skin, eyes and mucous membrane, pruritus , Fever, stomach / duodenal ulcer, inflammatory bowel disease and urge incontinence (Korea Patent Publication No. 10-2004-0034804), anti-obesity effect (Pharmacol. Rev., 1986, 38, 179), etc. Has been mentioned.

  Due to the pharmacological mechanism, both VR1 agonists and antagonists can be used as therapeutic agents for the aforementioned diseases. The analgesic effect of VR1 agonists has a pharmacological mechanism based on the desensitization of capsaicin-sensitive sensory nerves. In other words, it is a method that blocks pain caused by other noxious stimuli by inducing pain and stimulation in sensory nerves and desensitizing nerve cells, and is currently limited to local therapeutic agents due to the disadvantage of inducing initial pain It is a fact that has been developed. On the other hand, VR1 antagonists have a mechanism that blocks the pain signal recognition stage of sensory nerves, and since there are no problems of initial pain and stimulation induction, they are mainly studied as therapeutic agents for the treatment of systemic related diseases. ing.

  The current state of research on VR1 activity-modulating compounds is that agents such as capsaicin, DA-5018, and resiniferatoxin are used as pain treatment agents or are in clinical research (Szallasi, J. Med chem., 2004). , 47, 2717), and more than 20 antagonists such as capsazepine and iodoresiniferatoxin are under active preclinical research (WO0208221, WO03062209, WO2004055003, WO2004055004, WO2004002983, WO0216317, WO2004035549, WO2004014871, WO03099284, WO03022809). , WO02090326, WO02072536, WO03068749, WO2004033435, WO02076946, WO0095420, WO03055484, WO03014064, WO03080578, WO03097586, WO03070247, WO03029199).

  The novel benzimidazole derivative provided in the present invention is a compound characterized by having an excellent VR-1 antagonistic effect and has a completely different chemical structure from the VR1 antagonists reported to date.

  The compounds belonging to the present invention mainly have VR1 antagonistic activity as such, but do not exclude the possibility that a product of a metabolic process or the like exhibits a pharmacological action as an active agent after being absorbed into the body due to a special body environment. .

  The inventors have conducted extensive research on compounds that modulate the activity of VR-1. As a result, it was revealed that the novel benzimidazole derivative is an excellent VR-1 antagonist. In addition, the present invention was completed by confirming the strong pharmacological effects (pain, inflammation and anti-ulcer effects) and excellent safety of these derivatives in animal models.

Therefore, an object of the present invention is to provide a novel benzimidazole derivative or a non-toxic salt or solvate thereof having an activity suppressing effect excellent in VR-1.
Another object of the present invention is to provide a method for producing a novel benzimidazole derivative or a non-toxic salt or solvate thereof.

  Another object of the present invention is to provide a pharmaceutical composition having a VR-1 activity inhibitory effect comprising a novel benzimidazole derivative or a non-toxic salt or solvate thereof as an active ingredient.

  In order to achieve the above object, as one embodiment, the present invention provides a novel benzimidazole derivative compound represented by the following chemical formula 1.

R ¹ is hydrogen; lower alkyl having 1 to 8 carbons; lower alkenyl having 2 to 6 carbons; lower alkoxy having 1 to 8 carbons; haloalkyl having 1 to 6 carbons; haloalkoxy having 1 to 6 carbons; halogen atoms; nitro; hydroxy; hydroxymethyl, cyano, amino uncoated or substituted are mono- or di-substituted by alkyl having 1 to 6 carbon atoms, or amide; or is substituted by one or more R ^a or Unsubstituted cycloalkyl, pyridine, pyrimidine, pyrazole, pyrazine, phenyl, benzyl, imidazole, morpholine, benzodioxole, benzothiazole, benzimidazole, indole, pyrazolone, thiophene, furan, thiazole, isothiazole, oxazole, iso Oxazole, triazole, oxodiazole, thia Be or _{(CH 2)} p Ar groups; azoles, indazole, pyrrolidine, chromonyl, piperidine, morpholine ethyl, dihydropyrazole or pyrrole group;
Each R ^a is a lower alkyl having 1 to 8 carbon atoms; a lower alkenyl having 2 to 6 carbon atoms; a lower alkoxy having 1 to 8 carbon atoms; a haloalkyl having 1 to 6 carbon atoms; a haloalkoxy having 1 to 6 carbon atoms; Independently selected from the group consisting of: a halogen atom; nitro; hydroxyl; cyano; or amino, amide or sulfonamide mono-, di-substituted or unsubstituted with alkyl having 1 to 6 carbons;

A is O, NH, NHCO, CO, CO ₂ , SO, SO ₂ or NHSO ₂ ;
n is an integer of 0 or 1;
W is N or CR ³ ;
X is N or CR ⁴ ;

R ² is hydrogen; lower alkyl having 1 to 8 carbons; lower alkenyl having 2 to 6 carbons; lower alkoxy having 1 to 8 carbons; haloalkyl having 1 to 6 carbons; haloalkoxy having 1 to 6 carbons; Nitro; hydroxy; hydroxymethyl; cyano; phosphoric acid; phosphate ester; amino or amide mono- or disubstituted with lower alkyl having 1 to 6 carbon atoms; sulfanyl; sulfone; sulfoxide; sulfonamide; urea, carbamate , Carbonate; ketone; ester; carboxylic acid; methoxyethanol group; cycloalkyl, pyridine, pyrimidine, pyrazole, pyrazine, phenyl, benzyl, imidazole, morpholine substituted or unsubstituted with one or more R ^b , Benzodioxole, benzothiazole, benzimidazole Lumpur, indole, pyrazolone, thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, triazole, oxadiazole, thiadiazole, indazole, pyrrolidine, chromonyl, piperidine, be morpholine ethyl or dihydropyrazole groups;

Each R ^b is a lower alkyl having 1 to 8 carbon atoms; a lower alkenyl having 2 to 6 carbon atoms; a lower alkoxy having 1 to 8 carbon atoms; a haloalkyl having 1 to 6 carbon atoms; a haloalkoxy having 1 to 6 carbon atoms; Nitro; hydroxyl; cyano; sulfanyl, sulfone, sulfoxide, sulfonamide, urea, carbamate, carbonate, ketone, ester, carvone, mono-, di-substituted or unsubstituted with lower alkyl having 1 to 6 carbon atoms Independently selected from the group consisting of: acid, amino or amide;

R ³ and R ⁴ may be the same or different and are each independently hydrogen; lower alkyl having 1 to 8 carbons; lower alkenyl having 2 to 6 carbons; lower alkoxy having 1 to 6 carbons; carbon Haloalkyl having 1 to 6 carbon atoms, haloalkoxy having 1 to 6 carbon atoms, halogen atom, nitro, hydroxy, cyano, sulfanyl, sulfone, sulfoxide, sulfonamide, urea, carbamate, carbonate, ketone, ester, carboxylic acid, carbon number 1 Amino or amide mono- or di-substituted or unsubstituted with ~ 3 alkyl; or a phenyl or benzyl group substituted or unsubstituted with R ^c ; or R ³ and R ⁴ together Mono-, di-, tri-, or tetra-substituted with nitrogen, oxygen, or sulfur atoms, or saturated, partially saturated, or unsubstituted 5, 6 or 7-membered heterocyclic monocyclic unsaturated, or form a 6,7,8,9,10 or 11 membered heterobicyclic compounds;
R ^c represents a lower alkyl having 1 to 6 carbon atoms; a lower alkenyl having 2 to 4 carbon atoms; a lower alkoxy having 1 to 6 carbon atoms; a haloalkyl having 1 to 6 carbon atoms; a haloalkoxy having 1 to 6 carbon atoms; Selected from the group consisting of:

Q ¹ is N or CR ⁶ ;
Q ² is N or CR ⁷ ;
Q ³ is N or CR ⁸ ;
Q ⁴ is N or CR ⁹ ;
Ar is

Chosen from
p is an integer of 0, 1, 2, 3 or 4;
R ⁶ , R ⁷ , R ⁸ and R ⁹ may be the same or different and are each independently hydrogen; lower alkyl having 1 to 8 carbons; lower alkenyl having 2 to 6 carbons; 8 lower alkoxy; 1 to 6 haloalkyl; 1 to 6 haloalkoxy; halogen atom; nitro; hydroxy; hydroxymethyl; cyano; mono- or di-substituted with 1 to 6 lower alkyl Or unsubstituted amino or amide; sulfanyl; sulfone; sulfoxide; sulfonamide; urea; carbamate; carbonate; ketone; ester; carboxylic acid; or substituted with one or more ^Rd or unsubstituted Cycloalkyl, pyridine, pyrimidine, pyrazole, phenyl, benzyl, imidazole, morpholine, benzodioxide Sole, benzothiazole, benzimidazole, indole, pyrazolone, thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, triazole, oxodiazole, thiadiazole, indazole, thiomorpholine, thiazolidine, oxazolidine, pyrrolidine, chromonyl, piperidine, morpholine Is an ethyl or dihydropyrazole group; or

Any two of R ⁶ , R ⁷ , R ⁸ and R ^{9 taken} together are mono-, di-, tri- or tetra-substituted with nitrogen, oxygen, or sulfur atoms, or unsubstituted, substituted, Forming a partially saturated or unsaturated 5-, 6- or 7-membered heteromonocyclic or 6, 7, 8, 9, 10 or 11-membered heterobicyclic compound;
Each R ^d is a lower alkyl having 1 to 8 carbon atoms; a lower alkenyl having 2 to 6 carbon atoms; a lower alkoxy having 1 to 8 carbon atoms; a haloalkyl having 1 to 6 carbon atoms; a haloalkoxy having 1 to 6 carbon atoms; Nitro; hydroxy; cyano; amino, amide, sulfanyl, sulfone, sulfoxide, sulfonamide, urea, carbamate; carbonate, ketone; mono-, di-substituted or unsubstituted with lower alkyl having 1 to 6 carbon atoms An ester or a carboxylic acid;

R ¹⁰ , R ¹¹ and R ¹² may be the same or different and are each independently hydrogen; lower alkyl having 1 to 8 carbons; cycloalkyl; lower alkenyl having 2 to 6 carbons; 6 lower alkoxy; C 1-6 haloalkyl; C 1-6 haloalkoxy; halogen atom; nitro; hydroxy; hydroxymethyl; cyano; sulfanyl; sulfone; sulfoxide; An amino, amide, carboxylic acid or carboxylic acid ester group mono- or di-substituted with lower alkyl having 1 to 3 carbon atoms or unsubstituted; or within R ¹⁰ , R ¹¹ and R ¹² ; Any two can combine to form a saturated or unsaturated heteromonocyclic or heterobicyclic compound. The

As a preferred embodiment, the novel benzimidazole derivative compound of the present invention includes the compound of Formula 1 or an isomer thereof,
2- [4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
6-chloro-2- [4- (3-chloropyridin-2-yl) phenyl] -1H-benzimidazole,
6-tert-butyl-2- [4- (3-chloropyridin-2-yl) phenyl] -1H-benzimidazole,
2- [4- (3-chloropyridin-2-yl) phenyl] -6-fluoro-1H-benzimidazole,
2- [4- (3-chloropyridin-2-yl) phenyl] -6-methoxy-1H-benzimidazole,
4-chloro-2- [4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
2- [4- (3-chloropyridin-2-yl) phenyl] -4,6-bistrifluoromethyl-1H-benzimidazole,
2- [4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-imidazo [4,5-b] pyridine,
2- [4- (3-chloropyridin-2-yl) phenyl] -3H-imidazo [4,5-b] pyridine,
2- [4- (3-chloropyridin-2-yl) phenyl] -6,7-dimethyl-1H-benzimidazole,

2- [4- (3-chloropyridin-2-yl) phenyl] -1H-benzimidazole,
2- [4- (3-chloropyridin-2-yl) phenyl] -5,6-dichloro-1H-benzimidazole,
6-bromo-2- (4- (3-chloropyridin-2-yl) phenyl) -1H-benzimidazole,
4-bromo-2- (4- (3-chloropyridin-2-yl) phenyl) -6- (trifluoromethyl) -1H-benzimidazole,
6-bromo-2- (4- (3-chloropyridin-2-yl) phenyl-1H-imidazo [4,5-b] pyridine,
4,6-dibromo-2- [4- (3-chloropyridin-2-yl) phenyl] -1H-benzimidazole,
2- [4- (3-chloropyridin-2-yl) phenyl] -6-morpholin-4-yl-1H-benzimidazole,
2- [4- (3-chloropyridin-2-yl) phenyl] -6-thiomorpholin-4-yl-1H-benzimidazole,
2- [4- (3-chloropyridin-2-yl) phenyl] -4-morpholin-4-yl-6-trifluoromethyl-1H-benzimidazole,
2- [4- (3-chloropyridin-2-yl) phenyl] -4-thiomorpholin-4-yl-6-trifluoromethyl-1H-benzimidazole,

2- [4- (3-chloropyridin-2-yl) phenyl] -4-pyrrolidin-1-yl-6-trifluoromethyl-1H-benzimidazole,
{2- [4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazol-4-yl} diethylamine,
2- [4- (3-chloropyridin-2-yl) phenyl] -6-morpholin-4-yl-1H-imidazo [4,5-b] pyridine,
2- [4- (3-chloropyridin-2-yl) phenyl] -6-pyrrolidin-1-yl-1H-imidazo [4,5-b] pyridine,
6-tert-butyl-2- [4- (3,5-dichloropyridin-2-yl) phenyl] -1H-benzimidazole,
2- [4- (3,5-dichloropyridin-2-yl) phenyl] -4,6-bistrifluoromethyl-1H-benzimidazole,
6-tert-butyl-2- [4- (3-chloro-5-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
2- [4- (3-chloro-5-trifluoromethylpyridin-2-yl) phenyl] -4,6-bistrifluoromethyl-1H-benzimidazole,
2- [4- (3-chloro-5-trifluoromethylpyridin-2-yl) phenyl] -5,7-bistrifluoromethyl-1H-benzimidazole,
N- [4 ′-(4,6-bistrifluoromethyl-1H-benzimidazol-2-yl) -3-fluorobiphenyl-4-yl] methanesulfonamide,

6-tert-butyl-2- [4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
4-chloro-6-trifluoromethyl-2- [4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
6-chloro-2- [4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
4,6-bistrifluoromethyl-2- [4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
6-trifluoromethyl-2- [4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-imidazo [4,5-b] pyridine,
5,6-dichloro-2- [4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
4-bromo-6- (trifluoromethyl) -2- (4- (3- (trifluoromethyl) pyridin-2-yl) phenyl) -1H-benzimidazole,
6-bromo-2- (4- (3- (trifluoromethyl) pyridin-2-yl) phenyl) -1H-benzimidazole,
6-fluoro-2- (4- (3- (trifluoromethyl) pyridin-2-yl) phenyl) -1H-benzimidazole,
6-bromo-2- (4- (3- (trifluoromethyl) pyridin-2-yl) phenyl-1H-imidazo [4,5-b] pyridine,

4,6-dibromo-2- [4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
6-morpholin-4-yl-2- [4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
6-thiomorpholin-4-yl-2- [4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
Diethyl- {2- [4- (3-trifluoromethylpyridin-2-yl) phenyl] -3H-benzimidazo-5-yl} amine,
4-morpholin-4-yl-6-trifluoromethyl-2- [4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
4-thiomorpholin-4-yl-6-trifluoromethyl-2- [4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
4-pyrrolidin-1-yl-6-trifluoromethyl-2- [4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
6-tert-butyl-2- (4-pyridin-2-ylphenyl) -1H-benzimidazole,
6- (trifluoromethyl) -2- (4- (pyridin-2-yl) phenyl) -1H-benzimidazole,
4-chloro-6- (trifluoromethyl) -2- (4- (pyridin-2-yl) phenyl) -1H-benzimidazole,

5,6-dichloro-2- (4- (pyridin-2-yl) phenyl) -1H-benzimidazole,
4,6-bis (trifluoromethyl) -2- (4- (pyridin-2-yl) phenyl) -1H-benzimidazole,
6-fluoro-2- (4- (pyridin-2-yl) phenyl) -1H-benzimidazole,
6-bromo-2- (4- (pyridin-2-yl) phenyl) -1H-imidazo [4,5-b] pyridine,
4,6-dibromo-2- (4-pyridin-2-ylphenyl) -1H-benzimidazole,
2- [4- (6-chloro-5-methylpyridazin-3-yl) phenyl] -4,6-bistrifluoromethyl-1H-benzimidazole,
2- [4- (6-chloro-5-methylpyridazin-3-yl) phenyl] -5,7-bistrifluoromethyl-1H-benzimidazole,
4-bromo-6- (trifluoromethyl) -2- (4- (4- (trifluoromethyl) pyrimidin-2-yl) phenyl) -1H-benzimidazole,
4,6-dibromo-2- [4- (4-trifluoromethylpyrimidin-2-yl) phenyl] -1H-benzimidazole,
6-tert-butyl-2- (4- (pyrimidin-2-yl) phenyl) -1H-benzimidazole,

2- (4- (6- (trifluoromethyl) -1H-benzimidazol-2-yl) phenyl) pyridine-3-carbonitrile,
2- (4- (6- (tert-butyl-1H-benzimidazol-2-yl) phenyl) pyridine-3-carbonitrile,
6 ′-(4,6-dibromo-1H-benzimidazol-2-yl)-[2,3 ′] bipyridyl-3-carbonitrile,
2- [4- (3-chloropyrazin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
6-tert-butyl-2- [4- (3-chloropyrazin-2-yl) phenyl] -1H-benzimidazole,
6-bromo-2- [4- (3-chloropyrazin-2-yl) phenyl] -1H-benzimidazole,
5,6-dichloro-2- [4- (3-chloropyrazin-2-yl) phenyl] -1H-benzimidazole,
6-bromo-2- [4- (3-chloropyrazin-2-yl) phenyl] -1H-imidazo [4,5-b] pyridine,
6-tert-butyl-2- [4- (3-chloropyridin-2-yl) -2-fluorophenyl] -1H-benzimidazole,
4-chloro-2- [4- (3-chloropyridin-2-yl) -2-fluorophenyl] -6-trifluoromethyl-1H-benzimidazole,

2- [4- (3-chloropyridin-2-yl) -2-fluorophenyl] -6-methoxy-1H-benzimidazole,
6-tert-butyl-2- [4- (3,5-dichloropyridin-2-yl) -2-fluorophenyl] -1H-benzimidazole,
4-chloro-2- [4- (3,5-dichloropyridin-2-yl) -2-fluorophenyl] -6-trifluoromethyl-1H-benzimidazole,
2- [4- (3,5-dichloropyridin-2-yl) -2-fluorophenyl] -4,6-bistrifluoromethyl-1H-benzimidazole,
4-chloro-2- [4- (3-chloro-5-trifluoromethylpyridin-2-yl) -2-fluorophenyl] -6-trifluoromethyl-1H-benzimidazole,
2- [4- (3-chloro-5-trifluoromethylpyridin-2-yl) -2-fluorophenyl] -6-trifluoromethyl-1H-imidazo [4,5-b] pyridine,
2- [4- (3-chloro-5-trifluoromethylpyridin-2-yl) -2-fluorophenyl] -6-methoxy-1H-benzimidazole,
N- [3,3′-difluoro-4 ′-(6-methoxy-1H-benzimidazol-2-yl) biphenyl-4-yl] methanesulfonamide,
2- [2-fluoro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
6-tert-butyl-2- [2-fluoro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,

6-chloro-2- [2-fluoro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
5-chloro-2- [2-fluoro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
4-chloro-2- [2-fluoro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
7-chloro-2- [2-fluoro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -5-trifluoromethyl-1H-benzimidazole,
2- (2-fluoro-4-pyridin-2-yl) phenyl-6-trifluoromethyl-1H-benzimidazole,
6-tert-butyl-2- (2-fluoro-4-pyridin-2-yl) phenyl-1H-benzimidazole,
6-chloro-2- (2-fluoro-4-pyridin-2-yl) phenyl-1H-benzimidazole,
2- (2-fluoro-4-pyridin-2-yl) phenyl-4,6-bistrifluoromethyl-1H-benzimidazole,
2- [2-chloro-4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
4-chloro-2- [2-chloro-4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,

2- [2-chloro-4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-imidazo [4,5-b] pyridine,
2- [2-chloro-4- (3,5-dichloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
4-chloro-2- [2-chloro-4- (3,5-dichloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
2- [2-chloro-4- (3,5-dichloropyridin-2-yl) phenyl] -4,6-bistrifluoromethyl-1H-benzimidazole,
2- [2-chloro-4- (3,5-dichloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-imidazo [4,5-b] pyridine,
2- [2-chloro-4- (3-chloro-5-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
4-chloro-2- [2-chloro-4- (3-chloro-5-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
N- [4 ′-(6-tert-butyl-1H-benzimidazol-2-yl) -3′-chloro-3-fluorobiphenyl-4-yl] methanesulfonamide,
N- [3′-chloro-4 ′-(4-chloro-6-trifluoromethyl-1H-benzimidazol-2-yl) -3-fluorobiphenyl-4-yl] methanesulfonamide,
N- [4 ′-(4,6-bistrifluoromethyl-1H-benzimidazol-2-yl) -3′-chloro-3-fluorobiphenyl-4-yl] methanesulfonamide,

2- [2-chloro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
4-chloro-2- [2-chloro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
2- [2-chloro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -4,6-bistrifluoromethyl-1H-benzimidazole,
6-tert-butyl-2- [2-chloro-4- (3-methylpyridin-2-yl) phenyl] -1H-benzimidazole,
6-chloro-2- (2-chloro-4-pyridin-2-ylphenyl) -1H-benzimidazole,
2- (2-chloro-4-pyridin-2-ylphenyl) -6-trifluoromethyl-1H-imidazo [4,5-b] pyridine,
2- (2-chloro-4-pyridin-2-ylphenyl) -6-methoxy-1H-benzimidazole,
2- [4- (3-chloropyridin-2-yl) naphthalen-1-yl] -6-trifluoromethyl-1H-benzimidazole,
6-tert-butyl-2- [4- (3-chloropyridin-2-yl) naphthalen-1-yl] -1H-benzimidazole,
2- [4- (3-chloropyridin-2-yl) naphthalen-1-yl] -4,6-bistrifluoromethyl-1H-benzimidazole,

2- [4- (3-chloropyridin-2-yl) naphthalen-1-yl] -6-trifluoromethyl-1H-imidazo [4,5-b] pyridine,
6-tert-butyl-2- [4- (3,5-dichloropyridin-2-yl) naphthalen-1-yl] -1H-benzimidazole,
2- [4- (3,5-dichloropyridin-2-yl) naphthalen-1-yl] -4,6-bistrifluoromethyl-1H-benzimidazole,
6-tert-butyl-2- [4- (3-chloro-5-trifluoromethylpyridin-2-yl) naphthalen-1-yl] -1H-benzimidazole,
2- [4- (3-chloro-5-trifluoromethylpyridin-2-yl) naphthalen-1-yl] -4,6-bistrifluoromethyl-1H-benzimidazole,
N- {4- [4- (4,6-bistrifluoromethyl-1H-benzimidazol-2-yl) naphthalen-1-yl] -2-fluorophenyl} methanesulfonamide,
6-trifluoromethyl-2- [4- (3-trifluoromethylpyridin-2-yl) naphthalen-1-yl] -1H-benzimidazole,
6-tert-butyl-2- (4-pyridin-2-ylnaphthalen-1-yl) -1H-benzimidazole,
2- (4-pyridin-2-ylnaphthalen-1-yl) -4,6-bistrifluoromethyl-1H-benzimidazole,
6-tert-butyl-2- [3-chloro-4- (3-chloropyridin-2-yl) phenyl] -1H-benzimidazole,

2- [3-chloro-4- (3,5-dichloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
6-tert-butyl-2- [3-chloro-4- (3,5-dichloropyridin-2-yl) phenyl] -1H-benzimidazole,
2- [3-chloro-4- (3,5-dichloropyridin-2-yl) phenyl] -6-methoxy-1H-benzimidazole,
2- [3-chloro-4- (3,5-dichloropyridin-2-yl) phenyl] -5-methoxy-1H-benzimidazole,
2- [3-chloro-4- (3-chloro-5-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
6-tert-butyl-2- [3-chloro-4- (3-chloro-5-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
2- [3-chloro-4- (3-chloro-5-trifluoromethylpyridin-2-yl) phenyl] -6-methoxy-1H-benzimidazole,
2- [3-chloro-4- (3-chloro-5-trifluoromethylpyridin-2-yl) phenyl] -5-methoxy-1H-benzimidazole,
N- [2′-chloro-4 ′-(4-chloro-6-trifluoromethyl-1H-benzimidazol-2-yl) -3-fluorobiphenyl-4-yl] methanesulfonamide,
N- [4 ′-(4,6-bistrifluoromethyl-1H-benzimidazol-2-yl) -2′-chloro-3-fluorobiphenyl-4-yl] methanesulfonamide,

2- (3-chloro-4-pyridin-2-ylphenyl) -6-trifluoromethyl-1H-benzimidazole,
6-tert-butyl-2- (3-chloro-4-pyridin-2-ylphenyl) -1H-benzimidazole,
6-chloro-2- (3-chloro-4-pyridin-2-ylphenyl) -1H-benzimidazole,
4-chloro-2- (3-chloro-4-pyridin-2-ylphenyl) -6-trifluoromethyl-1H-benzimidazole,
5,6-dichloro-2- (3-chloro-4- (pyridin-2-yl) phenyl) -1H-benzimidazole,
6-bromo-2- (3-chloro-4- (pyridin-2-yl) phenyl) -1H-benzimidazole,
2- [3-chloro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
6-tert-butyl-2- [3-chloro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
6-chloro-2- [3-chloro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
2- [3-chloro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -6-methoxy-1H-benzimidazole,

2- [3-chloro-4- (3-methylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
3-chloro-6 ′-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine,
3-chloro-6 ′-(6-chloro-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine,
3-chloro-6 ′-(4-chloro-6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine,
6 ′-(4,6-bistrifluoromethyl-1H-benzimidazol-2-yl) -3-chloro- [2,3 ′] bipyridine,
4-bromo-2- (5- (3-chloropyridin-2-yl) pyridin-2-yl) -6- (trifluoromethyl) -1H-benzimidazole,
6-bromo-2- (5- (3-chloropyridin-2-yl) pyridin-2-yl) -1H-benzimidazole,
6 ′-(6-tert-butyl-1H-benzimidazol-2-yl) -3-chloro- [2,3 ′] bipyridine,
3-chloro-6 ′-(5,6-dichloro-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine,
3-chloro-6 ′-(4,6-dibromo-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine,

6 ′-(6-bromo-1H-imidazo [4,5-b] pyridin-2-yl) -3-chloro- [2,3 ′] bipyridine,
3-chloro-6 ′-(6-morpholin-4-yl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine,
3-chloro-6 ′-(6-thiomorpholin-4-yl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine,
3-chloro-6 ′-(4-morpholin-4-yl-6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine,
3-chloro-6 ′-(4-thiomorpholin-4-yl-6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine,
3-chloro-6 ′-(4-pyrrolidin-1-yl-6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine,
3,5-dichloro-6 ′-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine,
6 ′-(6-tert-butyl-1H-benzimidazol-2-yl) -3,5-dichloro- [2,3 ′] bipyridine,
3,5-dichloro-6 ′-(6-chloro-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine,
3,5-dichloro-6 ′-(4-chloro-6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine,

6 ′-(4,6-bistrifluoromethyl-1H-benzimidazol-2-yl) -3,5-dichloro- [2,3 ′] bipyridine,
6 ′-(4,6-bistrifluoromethyl-1H-benzimidazol-2-yl) -3-chloro-5-trifluoromethyl- [2,3 ′] bipyridine,
6 ′-(6-methoxy-1H-benzimidazol-2-yl) -3-chloro-5-trifluoromethyl- [2,3 ′] bipyridine,
3-trifluoromethyl-6 ′-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine,
6 ′-(6-tert-butyl-1H-benzimidazol-2-yl) -3-trifluoromethyl- [2,3 ′] bipyridine,
6 ′-(6-chloro-1H-benzimidazol-2-yl) -3-trifluoromethyl- [2,3 ′] bipyridine,
6 ′-(4-chloro-6-trifluoromethyl-1H-benzimidazol-2-yl) -3-trifluoromethyl- [2,3 ′] bipyridine,
6 ′-(5-trifluoromethyl-7-chloro-1H-benzimidazol-2-yl) -3-trifluoromethyl- [2,3 ′] bipyridine,
6 ′-(4,6-bistrifluoromethyl-1H-benzimidazol-2-yl) -3-trifluoromethyl- [2,3 ′] bipyridine,
6 ′-(5,6-dichloro-1H-benzimidazol-2-yl) -3-trifluoromethyl- [2,3 ′] bipyridine,

4-bromo-6- (trifluoromethyl) -2- (5- (3- (trifluoromethyl) pyridin-2-yl) pyridin-2-yl) -1H-benzimidazole,
6-bromo-2- (5- (3- (trifluoromethyl) pyridin-2-yl) pyridin-2-yl) -1H-benzimidazole,
6-fluoro-2- (5- (3- (trifluoromethyl) pyridin-2-yl) pyridin-2-yl) -1H-benzimidazole,
6 ′-(6-bromo-1H-imidazo [4,5-b] pyridin-2-yl) -3-trifluoromethyl [2,3 ′] bipyridine,
6 ′-(4,6-dibromo-1H-benzimidazol-2-yl) -3-trifluoromethyl- [2,3 ′] bipyridine,
6 ′-(6-morpholin-4-yl-1H-benzimidazol-2-yl) -3-trifluoromethyl- [2,3 ′] bipyridine,
6 ′-(4-morpholin-4-yl-6-trifluoromethyl-1H-benzimidazol-2-yl) -3-trifluoromethyl- [2,3 ′] bipyridine,
6 ′-(6-chloro-1H-benzoimidazol-2-yl)-[2,3 ′] bipyridine,
6 ′-(6-trifluoromethyl-1H-imidazo [4,5-b] pyridin-2-yl)-[2,3 ′] bipyridine,
5,6-dichloro-2- (5- (pyridin-2-yl) pyridin-2-yl) -1H-benzimidazole,

6-tert-butyl-2- (6-naphthalen-1-ylpyridin-3-yl) -1H-benzimidazole,
2- (6-naphthalen-1-ylpyridin-3-yl) -4,6-bistrifluoromethyl-1H-benzimidazole,
2- (6-naphthalen-1-ylpyridin-3-yl) -5,7-bistrifluoromethyl-1H-benzimidazole,
6- (trifluoromethyl) -2- (6- (naphthalen-1-yl) pyridin-3-yl) -1H-benzimidazole,
6-chloro-2- (6- (naphthalen-1-yl) pyridin-3-yl) -1H-benzimidazole,
2- (4-pyrrol-1-ylphenyl) -6-trifluoromethyl-1H-benzimidazole,
2- (4-pyrrol-1-ylphenyl) -3H-imidazo [4,5-b] pyridine,
6-chloro-2- (4-pyrrol-1-ylphenyl) -1H-benzimidazole,
6-tert-butyl-2- (4-pyrrol-1-ylphenyl) -1H-benzimidazole,
6-fluoro-2- (4-pyrrol-1-ylphenyl) -1H-benzimidazole,

2-biphenyl-4-yl-6-trifluoromethyl-1H-benzimidazole,
2-biphenyl-4-yl-3H-imidazo [4,5-b] pyridine,
2-biphenyl-4-yl-6-chloro-1H-benzimidazole,
2-biphenyl-4-yl-6-tert-butyl-1H-benzimidazole,
2-biphenyl-4-yl-6-fluoro-1H-benzimidazole,
2-biphenyl-4-yl-6-methoxy-1H-benzimidazole,
2- (4-phenoxyphenyl-6-trifluoromethyl) -1H-benzimidazole,
2- (4-phenoxyphenyl) -3H-imidazo [4,5-b] pyridine,
6-chloro-2- (4-phenoxyphenyl) -1H-benzimidazole,
6-tert-butyl-2- (4-phenoxyphenyl) -1H-benzimidazole,

6-fluoro-2- (4-phenoxyphenyl) -1H-benzimidazole,
6-methoxy-2- (4-phenoxyphenyl) -1H-benzimidazole,
2- [3- (4-chloropyrazol-1-ylmethyl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
6-chloro-2- [3- (4-chloropyrazol-1-ylmethyl) phenyl] -1H-benzimidazole,
6-tert-butyl-2- [3- (4-chloropyrazol-1-ylmethyl) phenyl] -1H-benzimidazole,
2- [3- (4-chloropyrazol-1-ylmethyl) phenyl] -6-fluoro-1H-benzimidazole,
Phenyl- [4- (6-trifluoromethyl-1H-benzimidazol-2-yl) phenyl] methanone,
[4- (6-tert-butyl-1H-benzimidazol-2-yl) phenyl] phenylmethanone,
2- [4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole hydrochloride,
6-tert-butyl-2- [4- (3-chloropyridin-2-yl) phenyl] -1H-benzimidazole hydrochloride,

6-tert-butyl-2- [4- (3-chloropyridin-2-yl) naphthalen-1-yl] -1H-benzimidazole hydrochloride,
6 ′-(4,6-bistrifluoromethyl-1H-benzimidazol-2-yl) -3-chloro [2,3 ′] bipyridine hydrochloride,
3-trifluoromethyl-6 ′-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine hydrochloride,
6-tert-butyl-2- [4- (3-chloropyridin-2-yl) phenyl] -1H-benzimidazole sodium salt,
3-trifluoromethyl-6 ′-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine sulfate,
3-trifluoromethyl-6 ′-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine phosphate,
3-trifluoromethyl-6 ′-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridinemethanesulfonate,
3-trifluoromethyl-6 ′-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridinebenzenesulfonate,
including.

  In yet another aspect, the present invention provides a method for producing the compound represented by Formula 1. This compound can be chemically synthesized by the method shown in the following reaction formula, but is not limited to the examples. The following reaction scheme shows a typical method for producing a compound of the present invention, and other compounds can be produced by appropriate changes in reagents and starting materials well known to those skilled in the art.

  In addition, since some compounds of Formula 1 have asymmetric centers, they can exist as enantiomeric forms, including all optical isomers, R or S-type stereoisomers of the compound of Formula 1, racemic pairs, and Enantiomers are also included within the scope of this invention. The present invention includes the use of racemates, one or more enantiomers, one or more diastereoisomers, or mixtures thereof, and includes methods for separating or producing the isomers.

Still another object of the present invention is to provide a pharmaceutical composition comprising an effective amount of the compound of formula 1 as an active ingredient together with a pharmaceutically acceptable carrier.
The method for producing the compound of Formula 1 is illustrated as described in Reaction Scheme 1 below.

  As shown in Reaction Scheme 1, the benzoic acid derivative (IX) for obtaining the target compound benzimidazole compound 1 is a commercially available halogen compound (II), a commercially available boronic acid (III), and a palladium catalyst. It can be produced by irradiation with microwaves under general reaction conditions in the presence of a base (Tapolcsanyi et. Al., Tetrahedron, 2002, 58, 10137).

  If the boronic acid is not commercially available, it can be produced by oxidation with methylboronic acid (V) (Sharma et. Al., Bioorg. Med. Chem. Lett. 1998, 8, 3459-3464) or methylboronic acid ( The benzoic acid derivative (IX) can be produced by reacting V) with the halogen compound (II) and then performing an oxidation reaction.

  Alternatively, it can be produced by reacting halobenzoic acid (VIII) with a commercially available boronic acid (VII), or a commercially available benzoic acid (X) can be used.

A benzoic acid derivative synthesized as described above or obtained as a commercial product is converted into a diamine derivative (IX) and O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium. After the amide compound as an intermediate is synthesized by condensation in the presence of hexafluorophosphate, the benzimidazole compound 1 as the target compound can be produced by performing a cyclization reaction without a separation and purification step. In this case, acetic acid, aqueous hydrochloric acid (Roglic et. Al., Pharmazie, 2001, 56, 803), POCl ₃ (Ries, et. Al., J. Med. Chem, 1993, 36, 4040), polyphosphoric acid (Ries , et. al., J. Med. Chem, 1993, 36, 4040), in the presence of pyridine (Abha et. al., Indian Journal of Chemistry, 2002, 41, 1978), or micro Benzimidazole compound 1 can be produced by irradiation with a wave (Lu, et. Al., Syn. Comm. 2002, 32, 3703).

  As indicated above, the compound of Formula 1 may be in the form of a salt, particularly a pharmaceutically acceptable salt. Pharmaceutically acceptable salts suitable for use in the present invention are those commonly used in the art, such as acid addition salts, and are described in the literature (J. Pharm. Sci., 1977, 66, 1). Including those disclosed in.

  Pharmaceutically acceptable acid addition salts suitable for use in the present invention include inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, orthophosphoric acid or sulfuric acid, and methanesulfonic acid, benzenesulfonic acid, for example. , Toluenesulfonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid, maleic acid, glycerophosphoric acid, or a salt to which an organic acid such as acetylsalicylic acid is added.

  A base can also be used to make a pharmaceutically acceptable metal salt. The alkali metal salt or alkaline earth metal salt is prepared by, for example, dissolving a compound in an excessive amount of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering an undissolved compound salt, and evaporating and drying the filtrate. Can be obtained. At this time, as the metal salt, it is particularly suitable to produce sodium, potassium or calcium salts, and the corresponding silver salts are alkali metal or alkaline earth metal salts which are suitable silver salts (for example, , Nitrate).

  Salts and / or solvates of the compound of Formula 1 that are not pharmaceutically acceptable are pharmaceutically acceptable salts and / or solvates of the compound of Formula 1 or the compound of Formula 1 itself. In production, it can be useful as an intermediate, in which case still another aspect of the present invention is constructed.

  The compound of Formula 1 can be produced in a crystalline form or an amorphous form, and can be optionally hydrated or solvated as long as it is in a crystalline form. Within the scope of the present invention are included compounds containing any number of water molecules as well as stoichiometric hydrates.

Suitable solvates include pharmaceutically acceptable solvates, such as hydrates.
Solvates include stoichiometric solvates and non-stoichiometric solvates.

  Since the compound of formula 1 and pharmaceutically acceptable salts thereof possess vanilloid receptor antagonist activity, the treatment or prevention of specific indications such as those indicated above, or related thereto There is a potential for use in the treatment of pain.

  Indications are pain, acute pain, chronic pain, neuropathic pain, postoperative pain, migraine, joint pain, neuropathy, nerve damage, diabetic neuropathy, neuropathic disease, neurodermatitis, stroke, Bladder hypersensitivity, irritable bowel syndrome, respiratory diseases such as asthma, chronic obstructive pulmonary disease, burns, psoriasis, pruritus, vomiting, skin, eye and mucous membrane irritation, gastric / duodenal ulcer, inflammation Examples thereof include sexual bowel disease and inflammatory disease.

  Accordingly, the present invention also provides a compound of formula 1 or a pharmaceutically acceptable salt or solvate thereof useful as an active ingredient, particularly in the treatment and prevention of the symptoms of the present invention.

  In particular, the present invention provides a compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof useful for the treatment or prevention of pain.

  In addition, the present invention provides a vanilloid receptor antagonistic action comprising administering a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof to a mammal having the above symptoms. Methods are provided for the treatment or prevention of beneficial symptoms.

  The present invention provides the use of a compound of formula 1 or a pharmaceutically acceptable salt or solvate thereof in the treatment or prevention of symptoms relating to a treatment in which antagonism of the vanilloid receptor is beneficial.

  In order to use a compound of the present invention in therapy, the compound is generally formulated into a pharmaceutical composition by standard pharmaceutical practice. Thus, the present invention includes a compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof and an additive such as a pharmaceutically acceptable carrier, adjuvant or diluent for the same. A pharmaceutical composition is provided. For example, the compounds of the present invention can be dissolved in oils, propylene glycol or other solvents commonly used in the preparation of injectable solutions. Suitable carriers are not particularly limited and include, for example, physiological saline, polyethylene glycol, ethanol, vegetable oils and isopropyl myristate. For topical action, the compounds of the invention can be formulated into ointments or creams.

Hereinafter, the dosage form method and the carrier will be described, but the present invention is not limited to these examples.
The pharmaceutical dosage forms of the compounds of the present invention can also be used in the form of their pharmaceutically acceptable salts or solvates and can be used alone or in any suitable conjugate with other pharmaceutically active compounds. Can be used in aggregates.

  The compounds of the present invention may be prepared by dissolving or suspending the compound in a water-soluble solvent such as physiological saline, 5% dextrose, or a water-insoluble solvent such as synthetic fatty acid glycerides, higher fatty acid esters or propylene glycol, or It can be emulsified. The dosage forms of the present invention can contain conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers and preservatives.

  The preferred dosage of the compound of the present invention varies depending on the condition and weight of the patient, the severity of the disease, the form of the drug, the administration route and the period, but can be appropriately selected by those skilled in the art. However, for a favorable effect, the compound of the present invention is administered at a dose of 0.0001-100 mg / kg body weight, desirably 0.001-100 mg / kg body weight per day. Administration can be carried out once a day or divided into several times.

  Depending on the method of administration, the pharmaceutical composition may contain 0.001 to 99% by weight, desirably 0.01 to 60% by weight, of a compound of the invention.

  The pharmaceutical composition of the present invention can be administered to mammals such as rabbits, mice, domestic animals and humans via various routes. All modes of administration can be envisaged, but can be administered for example by oral or rectal administration, intravenous, intramuscular, subcutaneous, endometrial or cerebrovascular injection.

Hereinafter, the present invention will be described in detail based on examples and experimental examples. However, the following examples and experimental examples are merely examples of the present invention and do not limit the contents of the present invention.
(Example)

Example 1. Preparation of 2- [4- (3-chloropyridin-2-yl) -phenyl] -6-trifluoromethyl-1H-benzimidazole compound

(1) Production of 4- (3-chloropyridin-2-yl) benzoic acid compound To 5.3 g (36.1 mmol) of 2,3-dichloropyridine dissolved in 200 mL of 1,2-dimethoxyethane and 200 mL of distilled water 22.3 g (0.21 mol) of Na ₂ CO ₃ , 5.0 g (30.1 mmol) of 4-carboxylphenylboronic acid and 0.5 g of Pd (PPh ₃ ) ₄ are added, and the mixture is stirred for 18 hours while heating under reflux. After cooling to room temperature and concentrating under reduced pressure to 50%, the aqueous layer is washed with ethyl acetate. The aqueous layer is adjusted to pH 1 with concentrated hydrochloric acid and extracted three times with ethyl acetate, and the organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated by column chromatography (developing solvent: chloroform / methanol = 10/1), and 5.3 g (yield 75%) of 4- (3-chloropyridin-2-yl) benzoic acid compound as a white precipitate. Got.
¹ H NMR (CD ₃ OD) δ: 8.57 (dd, 1H, J = 4.8, 1.4 Hz), 8.13 (dd, 2H, J = 6.9, 1.7 Hz), 8.03 (dd, 1H, J = 8.1, 1.4 Hz) ), 7.75 (dd, 2H, J = 6.9, 1.7Hz), 7.44 (dd, 1H, J = 8.1, 4.8Hz)

(2) Production of 4- (3-chloropyridin-2-yl) benzoic acid compound 0.5 g (2.45 mmol) of 3-chloro-p-tolyl-pyridine is dissolved in 5 mL of pyridine and 2.5 mL of distilled water is added. . To this was added 1.36 g (8.59 mmol) of potassium permanganate, and after stirring well so that potassium permanganate did not adhere to the surface of the vessel, a microwave reactor (manufactured by Initiator Sixty, Biotage) ) For 5 minutes at 100 ° C. When the reaction is complete, the reaction solution is filtered through celite to remove the solid. The filtered solution is concentrated under reduced pressure, and 10 mL of distilled water and 10 mL of ethyl acetate are added to the concentrated solution. In addition, 1.0N hydrochloric acid solution is added to raise the pH of the aqueous solution to 4.0 and then stirred for 40 minutes. The ethyl acetate layer is separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in a small amount of methanol and separated by column chromatography (chloroform / methanol = 10: 1) to obtain 0.35 g (yield 61%) of 4- (3-chloropyridin-2-yl) benzoic acid compound. It was.

(3) Preparation of 2- [4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound 4- (3-Chloropyridin-2 dissolved in 25 mL of dimethylformamide -Yl) benzoic acid 0.59 g (2.5 mmol), 4-trifluoromethylbenzene-1,2-diamine 0.44 g (2.5 mmol), diisopropylethylamine 1.0 mL (5.0 mmol) and O- (7 -Azabenzotriazol-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (1.1 g, 6 mmol) is added and stirred at room temperature for 16 hours. This is concentrated under reduced pressure, dissolved in ethyl acetate, washed with saturated NaHCO ₃ and saturated NaCl, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is dissolved in acetic acid / toluene (15 mL / 1.5 mL), stirred at 75 ° C. for 3 hours, and concentrated under reduced pressure. This is dissolved in ethyl acetate, washed with saturated NaHCO ₃ and saturated NaCl, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (developing solvent: chloroform / methanol = 30/1) to give 2- [4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzo 0.77 g (yield 82%) of an imidazole compound was obtained.
¹ H NMR (CDCl ₃ ) δ: 8.65 (m, 1H), 8.06 (d, 2H, J = 8.4 Hz), 7.93 (s, 1H), 7.85 (d, 1H, J = 8.2 Hz), 7.77 (d , 2H, J = 8.4Hz), 7.69 (d, 1H, J = 8.2Hz), 7.52 (d, 1H, J = 8.2Hz), 7.34-7.30 (m, 1H)

(4) Preparation of 2- [4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound 4- (3-Chloropyridine-2 dissolved in 30 mL of anhydrous pyridine -Yl) 0.44 g (2.5 mmol) of 4-fluoromethylbenzene-1,2-diamine is added to 0.58 g (2.5 mmol) of benzoic acid, and the mixture is stirred for 6 hours under heating and reflux. After cooling this to room temperature, cooling water (100 mL) containing HCl (10 mL) is added and allowed to stand for 30 minutes to obtain a precipitate. This precipitate was separated by column chromatography (developing solvent: chloroform / methanol = 30/1), and 2- [4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H— 0.70 g (yield 75%) of a benzimidazole compound was obtained.

(5) Preparation of 2- [4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound 4- (3-Chloropyridin-2 dissolved in 25 mL of 4N HCl -Yl) 0.44 g (2.5 mmol) of 4-trifluoromethylbenzene-1,2-diamine is added to 0.64 g (2.75 mmol) of benzoic acid and stirred at 180 ° C. for 6 hours. This is cooled to room temperature, 10% NaHCO ₃ (10 mL) is added and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated by column chromatography (developing solvent: chloroform / methanol = 30/1) to give 2- [4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzo 0.61 g (yield 65%) of an imidazole compound was obtained.

(6) Preparation of 2- [4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound 4- (3-Chloropyridin-2 dissolved in 20 mL of POCl ₃ -Yl) 0.44 g (2.5 mmol) of 4-trifluoromethylbenzene-1,2-diamine is added to 0.64 g (2.75 mmol) of benzoic acid, and the mixture is stirred for 3 hours under heating and reflux. After cooling to room temperature and dissolving in distilled water, ammonia is added to adjust to pH 8-10, and extraction is performed with ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated by column chromatography (developing solvent: chloroform / methanol = 30/1) to give 2- [4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzo 0.61 g (yield 65%) of an imidazole compound was obtained.

(7) Preparation of 2- [4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound 4- (3-Chloropyridine-2 dissolved in 25 g of polyphosphoric acid -Yl) 0.44 g (2.5 mmol) of 4-trifluoromethylbenzene-1,2-diamine is added to 0.70 g (3.0 mmol) of benzoic acid and stirred at 150 ° C. for 20 hours. This is cooled to room temperature, dissolved in distilled water, adjusted to pH 9, and a precipitate is produced. This precipitate was purified by column chromatography (developing solvent: chloroform / methanol = 30/1) to give 2- [4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H— 0.61 g (65% yield) of a benzimidazole compound was obtained.

(8) Preparation of 2- [4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound 4-Poly (3-chloropyridin-2-yl) in 10 mL of polyphosphoric acid After adding 0.70 g (3.0 mmol) of benzoic acid and 0.44 g (2.5 mmol) of 4-trifluoromethylbenzene-1,2-diamine, and stirring for 5 minutes, a microwave reactor (Initiator Sixty, Biotage) For 15 minutes. This is cooled to room temperature, 20 mL of distilled water is added, and an aqueous NaOH solution is gradually added while stirring to adjust the pH to neutral. The resulting precipitate was obtained by filtration and then separated by column chromatography (developing solvent: chloroform / methanol = 30/1) to give 2- [4- (3-chloropyridin-2-yl) phenyl]. 0.72 g (yield 77%) of -6-trifluoromethyl-1H-benzimidazole compound was obtained.

(9) Preparation of 2- [4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound 4- (3-Chloropyridine-2 dissolved in 25 mL of dimethylformamide -Yl) benzoic acid 0.59 g (2.5 mmol), 4-trifluoromethylbenzene-1,2-diamine 0.44 g (2.5 mmol), diisopropylethylamine 1.0 mL (5.0 mmol) and O- (7 -Azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (1.1 g, 6 mmol) was added and stirred for 5 minutes, and then the microwave reactor (Initiator Sixty, Biotage) for 15 minutes. This is concentrated under reduced pressure, dissolved in ethyl acetate, washed with saturated NaHCO ₃ and saturated NaCl, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is dissolved in acetic acid (15 mL), stirred for 5 minutes, and irradiated in a microwave reactor (Initiator Sixty, Biotage) for 15 minutes. This is cooled to room temperature, concentrated under reduced pressure, dissolved in ethyl acetate, washed with saturated NaHCO ₃ and saturated NaCl, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (developing solvent: chloroform / methanol = 30/1) to give 2- [4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzo 0.81 g (yield 90%) of an imidazole compound was obtained.

Examples 2-16
It carried out by the method similar to the said Example 1 (3), and obtained the compounds 2-16.

Example 17. Preparation of 2- [4- (3-chloropyridin-2-yl) phenyl] -6-morpholin-4-yl-1H-benzimidazole compound

To 162 mg (0.42 mmol) of 6-bromo-2- (4- (3-chloropyridin-2-yl) phenyl) -1H-benzimidazole dissolved in 6 mL of dichloromethane, 0.2 mL of N, N-dimethylisopropylethylamine ( 1.15 mmol) and 0.1 mL (0.57 mmol) of 2- (trimethylsilyl) ethoxymethyl chloride are added and stirred at room temperature for 16 hours. This was concentrated under reduced pressure, morpholine 26 μL (0.30 mmol), tris (dibenzylidineacetone) dipalladium (0) 56.3 mg (0.013 mmol), 2- (di-t-butylphosphino) biphenyl 10 mg (0 0.038 mmol) and 38.8 mg (0.41 mmol) of sodium-t-butoxide, dissolved in 2.5 mL of toluene, and reacted at 90 ° C. for 10 minutes in a microwave reactor. This is cooled to room temperature, dissolved in 5 mL of ethyl acetate, filtered through diatomaceous earth, the filtrate is dried over magnesium sulfate and concentrated under reduced pressure. This is further dissolved in 3 mL of a mixture of trifluoroacetic acid and methyllen chloride (1: 1) and then stirred for 12 hours. Neutralize with 10% aqueous NaOH, extract with ethyl acetate, dry over magnesium sulfate, and concentrate under reduced pressure. This residue was separated by column chromatography (developing solvent: hexane / ethyl acetate = 1/1) to give 2- [4- (3-chloropyridin-2-yl) phenyl] -6-morpholin-4-yl. 115 mg of -1H-benzimidazole compound (yield 70%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.64 (d, 1H), 8.18 (d, 2H), 8.10 (d, 1H), 7.87 (d, 2H), 7.66 (d, 1H), 7.61-7.45 (m , 2H), 7.21 (dd, 1H), 3.91-3.87 (m, 4H), 3.32-3.27 (m, 4H)

Examples 18-24
In the same manner as in Example 17, compounds 18 to 24 were obtained.

Example 25. Preparation of 6-tert-butyl-2- [4- (3,5-dichloropyridin-2-yl) phenyl] -1H-benzimidazole compound

(1) Preparation of 4- (3,5-dichloropyridin-2-yl) benzoic acid compound 4- (3,5-dichloropyridin-2-yl ester) was prepared in the same manner as in Example 1 (1). Yl) A benzoic acid compound (yield 79%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.74 (s, 1H), 8.27-8.24 (m, 3H), 7.92 (d, 2H)

(2) Production of 6-tert-butyl-2- [4- (3,5-dichloropyridin-2-yl) phenyl] -1H-benzimidazole compound In the same manner as (3) of Example 1 above. And 6-tert-butyl-2- [4- (3,5-dichloropyridin-2-yl) phenyl] -1H-benzimidazole compound (yield 90%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.62 (s, 1H), 8.20 (d, 2H), 8.15 (s, 1H), 7.88 (d, 2H), 7.64 (s, 1H), 7.56 (s, 1H ), 7.41 (d, 1H), 1.42 (s, 9H)

Example 26. Preparation of 2- [4- (3,5-dichloropyridin-2-yl) phenyl] -4,6-bistrifluoromethyl-1H-benzimidazole compound

2- [4- (3,5-dichloropyridin-2-yl) phenyl] -4,6-bistrifluoromethyl-1H-benzimidazole compound was prepared in the same manner as in Example 25 (2) above. Yield 72%).
¹ H NMR (CD ₃ OD) δ: 8.64 (d, 1H), 8.34 (d, 1H), 8.17-8.10 (m, 2H), 7.94 (d, 2H), 7.87-7.80 (m, 2H)

Example 27. Preparation of 6-tert-butyl-2- [4- (3-chloro-5-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole compound

(1) Production of 4- (3-chloro-5-trifluoromethylpyridin-2-yl) benzoic acid compound The same procedure as in Example 1 (1) was carried out to prepare 4- (3-chloro-5 -Trifluoromethylpyridin-2-yl) benzoic acid compound (yield 75%) was obtained.
¹ H NMR (CD ₃ OD) δ: 9.05 (d, 1H), 8.51 (d, 1H), 8.28 (dd, 2H), 7.97 (dd, 2H)

(2) Preparation of 6-tert-butyl-2- [4- (3-chloro-5-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole compound (3) of Example 1 above In the same manner, 6-tert-butyl-2- [4- (3-chloro-5-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole compound (yield 87%) was obtained. .
¹ H NMR (CD ₃ OD) δ: 8.93 (s, 1H), 8.38 (s, 1H), 8.23 (d, 2H), 7.95 (d, 2H), 7.69-7.50 (m, 2H), 7.44-7.39 (m, 1H), 1.42 (s, 9H)

Example 28. 2- [4- (3-Chloro-5-trifluoromethylpyridin-2-yl) phenyl] -4,6-bistrifluoromethyl-1H-benzimidazole and 2- [4- (3-chloro-5-trimethyl) Preparation of fluoromethylpyridin-2-yl) phenyl] -5,7-bistrifluoromethyl-1H-benzimidazole compound

2- [4- (3-Chloro-5-trifluoromethylpyridin-2-yl) phenyl] -4,6-bistrifluoromethyl-1H— was prepared in the same manner as in Example 27 (2). A benzimidazole compound and 2- [4- (3-chloro-5-trifluoromethylpyridin-2-yl) phenyl] -5,7-bistrifluoromethyl-1H-benzimidazole compound (yield 68%) were obtained. .
¹ H NMR (CD ₃ OD) δ: 8.95 (d, 0.7H), 8.92 (d, 0.3H), 8.40-8.35 (m, 2.0H), 8.18 (s, 0.7H), 8.16 (s, 0.3H ), 8.01-7.99 (m, 1.0H), 7.94-7.90 (m, 1H), 7.87 (d, 0.3H), 7.85 (d, 0.7H), 7.44 (s, 0.3H), 7.39 (d, 0.7 H)

Example 29. Preparation of N- [4 '-(4,6-bistrifluoromethyl-1H-benzimidazol-2-yl) -3-fluorobiphenyl-4-yl] methanesulfonamide compound

(1) Preparation of 4- (3-fluoro-4-methanesulfonylaminophenyl) benzoic acid compound 4- (3-fluoro-4-methanesulfonylamino) was prepared in the same manner as in Example 1 (1). A phenyl) benzoic acid compound (yield 58%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.22 (dd, 2H), 7.87 (dd, 2H), 7.77-7.64 (m, 3H), 3.18 (s, 3H)

(2) Production of N- [4 ′-(4,6-bistrifluoromethyl-1H-benzimidazol-2-yl) -3-fluorobiphenyl-4-yl] methanesulfonamide compound N- [4 ′-(4,6-bistrifluoromethyl-1H-benzoimidazol-2-yl) -3-fluorobiphenyl-4-yl] methanesulfonamide compound (yield) 62%).
¹ H NMR (CD ₃ OD) δ: 8.13 (d, 2H), 7.83 (d, 2H), 7.72 (s, 1H), 7.68-7.62 (m, 2H), 7.59-7.55 (m, 2H), 3.07 (s, 3H)

Example 30. FIG. Preparation of 6-tert-butyl-2- [4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole compound

(1) Production of 4- (3-trifluoromethylpyridin-2-yl) benzoic acid compound 4- (3-trifluoromethylpyridin-2-yl) was carried out in the same manner as (1) in Example 1 above. Yl) A benzoic acid compound (yield 84%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.84 (d, 1H), 8.30 (d, 1H), 8.11 (d, 2H), 7.68-7.64 (m, 1H), 7.56 (d, 2H)

(2) Production of 6-tert-butyl-2- [4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole compound In the same manner as (3) of Example 1 above. And 6-tert-butyl-2- [4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole compound (yield 93%) was obtained.
¹ H NMR (CDCl ₃ ) δ: 8.87 (d, 1H), 8.13 (s, 1H), 8.11 (d, 2H), 7.66 (s, 1H), 7.62 (d, 2H), 7.61 (s, 1H) , 7.50-7.47 (m, 1H), 7.36 (d, 1H), 1.39 (s, 9H)

Examples 31-40
It carried out by the method similar to the said Example 1 (3), and obtained the compounds 31-40.

Example 41. Preparation of 6-morpholin-4-yl-2- [4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole compound

6-morpholin-4-yl-2- [4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole compound (yield 73%) was prepared in the same manner as in Example 17. )
¹ H NMR (CD ₃ OD) δ: 8.85 (d, 1H), 8.32 (dd, 1H), 8.17 (d, 2H), 7.69-7.62 (m, 3H), 7.58 (d, 1H), 7.14 (d , 1H), 7.09 (dd, 1H), 3.83 (dt, 4H), 3.18 (dt, 4H)

Examples 42-46
In the same manner as in Example 41, compounds 42 to 46 were obtained.

Example 47. Preparation of 6-tert-butyl-2- (4-pyridin-2-ylphenyl) -1H-benzimidazole compound

(1) Production of 4- (pyridin-2-yl) benzoic acid compound 4- (pyridin-2-yl) benzoic acid compound (yield 80%) )
¹ H NMR (CD ₃ OD) δ: 8.66 (d, 1H), 8.14 (d, 2H), 8.07 (d, 2H), 7.94 (d, 2H), 7.43-7.40 (m, 1H)

(2) Production of 6-tert-butyl-2- (4-pyridin-2-ylphenyl) -1H-benzimidazole compound 6-tert-butyl was prepared in the same manner as in Example 1 (3). A 2- (4-pyridin-2-ylphenyl) -1H-benzimidazole compound (yield 84%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.69 (d, 1H), 8.22 (s, 4H), 7.98 (dd, 2H), 7.69 (d, 1H), 7.64 (d, 1H), 7.55 (dd, 1H ), 7.43 (dd, 1H), 1.41 (s, 9H)

Examples 48-54
In the same manner as in Example 47 (2), compounds 48 to 54 were obtained.

Example 55. 2- [4- (6-Chloro-5-methylpyridazin-3-yl) phenyl] -4,6-bistrifluoromethyl-1H-benzimidazole and 2- [4- (6-chloro-5-methylpyridazine- Preparation of 3-yl) phenyl] -5,7-bistrifluoromethyl-1H-benzimidazole compound

(1) Production of 4- (6-chloro-5-methylpyridazin-3-yl) benzoic acid compound 4- (6-chloro-5-methyl) was carried out in the same manner as in Example 1 (1). Pyridazin-3-yl) benzoic acid compound (yield 52%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.20 (s, 1H), 8.20-8.16 (m, 4H), 2.53 (s, 3H)

(2) 2- [4- (6-Chloro-5-methylpyridazin-3-yl) phenyl] -4,6-bistrifluoromethyl-1H-benzimidazole and 2- [4- (6-chloro-5- Preparation of methylpyridazin-3-yl) phenyl] -5,7-bistrifluoromethyl-1H-benzimidazole compound 2- [4- (6-Chloroform) was carried out in the same manner as in Example 1 (3). -5-methylpyridazin-3-yl) phenyl] -4,6-bistrifluoromethyl-1H-benzimidazole and 2- [4- (6-chloro-5-methylpyridazin-3-yl) phenyl] -5 A 7-bistrifluoromethyl-1H-benzimidazole compound (yield 71%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.89 (d, 0.5H), 8.64 (d, 0.5H), 8.45-8.37 (m, 2.5H), 8.33-8.15 (m, 2.5H), 7.70-7.60 ( m, 1.0H), 2.75 (s, 1.5H), 2.54 (s, 1.5H)

Example 56. Preparation of 4-bromo-6- (trifluoromethyl) -2- (4- (4- (trifluoromethyl) pyrimidin-2-yl) phenyl) -1H-benzimidazole compound

(1) Production of 4- (4-trifluoromethylpyrimidin-2-yl) benzoic acid compound 4- (4-trifluoromethylpyrimidin-2-yl) was carried out in the same manner as in Example 1 (1) above. Yl) A benzoic acid compound (yield 77%) was obtained.
¹ H NMR (CD ₃ OD) δ: 9.20 (d, 1H), 8.62 (dd, 2H), 8.19 (dd, 2H), 7.81 (d, 1H)

(2) Preparation of 4-bromo-6- (trifluoromethyl) -2- (4- (4- (trifluoromethyl) pyrimidin-2-yl) phenyl) -1H-benzimidazole compound 4-Bromo-6- (trifluoromethyl) -2- (4- (4- (trifluoromethyl) pyrimidin-2-yl) phenyl) -1H-benzimidazole compound (3) Yield 72%).
¹ H NMR (CDCl ₃ ) δ: 9.14 (d, 1H), 8.74 (d, 2H), 8.27 (d, 2H), 8.00 (s, 1H), 7.76 (s, 1H), 7.62 (d, 1H)

Example 57. Preparation of 4,6-dibromo-2- [4- (4-trifluoromethylpyrimidin-2-yl) phenyl] -1H-benzimidazole compound

4,6-Dibromo-2- [4- (4-trifluoromethylpyrimidin-2-yl) phenyl] -1H-benzimidazole compound (yield) was obtained in the same manner as in Example 56 (2). 64%).
¹ H NMR (CD ₃ OD) δ: 9.18 (d, 1H), 8.70 (dd, 1H), 8.56 (d, 2H), 8.36 (dd, 1H), 8.26 (s, 1H), 8.15 (d, 2H )

Example 58. Preparation of 6-tert-butyl-2- (4- (pyrimidin-2-yl) phenyl) -1H-benzimidazole compound

(1) Production of 4- (pyrimidin-2-yl) benzoic acid compound 4- (pyrimidin-2-yl) benzoic acid compound (yield 74%) was prepared in the same manner as in Example 1 (1). )
¹ H NMR (CD ₃ OD) δ: 8.88 (d, 2H), 8.47 (d, 2H), 8.12 (d, 2H), 7.39 (t, 1H)

(2) Production of 6-tert-butyl-2- (4- (pyrimidin-2-yl) phenyl) -1H-benzimidazole compound 6-tert-butyl was prepared in the same manner as in Example 1 (3). -Butyl-2- (4- (pyrimidin-2-yl) phenyl) -1H-benzimidazole compound (yield 92%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.88 (d, 2H), 8.58 (dd, 2H), 8.21 (dd, 2H), 7.64 (d, 1H), 7.56 (d, 1H), 7.42-7.37 (m , 2H), 1.41 (s, 9H)

Example 59. Preparation of 2- (4- (6- (trifluoromethyl) -1H-benzimidazol-2-yl) phenyl) pyridine-3-carbonitrile compound

(1) Production of 4- (3-cyanopyridin-2-yl) benzoic acid compound 4- (3-cyanopyridin-2-yl) benzoic acid was carried out in the same manner as (1) in Example 1 above. A compound (yield 59%) was obtained.
¹ H NMR (CD ₃ OD) δ: 9.04 (dd, 1H), 8.46 (dd, 1H), 8.32 (d, 2H), 8.12 (d, 2H), 7.74 (dd, 1H)

(2) Preparation of 2- (4- (6- (trifluoromethyl) -1H-benzimidazol-2-yl) phenyl) pyridine-3-carbonitrile compound A method similar to (3) of Example 1 above To give 2- (4- (6- (trifluoromethyl) -1H-benzimidazol-2-yl) phenyl) pyridine-3-carbonitrile compound (yield 76%).
¹ H NMR (CD ₃ OD) δ: 8.89 (dd, 1H), 8.32-8.26 (m, 3H), 8.08 (dd, 2H), 7.90 (s, 1H), 7.75 (d, 1H), 7.60-7.53 (m, 2H)

Examples 60 and 61
In the same manner as in Example 59 (2), compounds 60 and 61 were obtained.

Example 62. Preparation of 2- [4- (3-chloropyrazin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound

(1) Production of 4- (3-chloropyrazin-2-yl) benzoic acid compound 4- (3-chloropyrazin-2-yl) benzoic acid was prepared in the same manner as in Example 1 (1). A compound (yield 79%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.72 (d, 1H), 8.50 (d, 1H), 8.20 (d, 2H), 7.93 (d, 2H)

(2) Preparation of 2- [4- (3-chloropyrazin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound The same procedure as in (3) of Example 1 was performed. A 2- [4- (3-chloropyrazin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound (yield 96%) was obtained.
¹ H NMR (CDCl ₃ ) δ: 8.62 (d, 1H), 8.39 (d, 1H), 8.20 (d, 2H), 7.99 (s, 1H), 7.97 (d, 2H), 7.71 (s, 1H) , 7.52 (dd, 1H)

Examples 63-66
In the same manner as in Example 62 (2), compounds 63 to 66 were obtained.

Example 67. Preparation of 6-tert-butyl-2- [4- (3-chloropyridin-2-yl) -2-fluorophenyl] -1H-benzimidazole compound

(1) Production of 4- (3-chloropyridin-2-yl) -2-fluorobenzoic acid compound 4- (3-chloropyridin-2-one) was prepared in the same manner as in (1) of Example 1 above. Yl) -2-fluorobenzoic acid compound (yield 77%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.51 (d, 1H), 7.99-7.93 (m, 2H), 7.52-7.48 (m, 2H), 7.42-7.36 (m, 1H), 1.42 (s, 9H)

(2) Production of 6-tert-butyl-2- [4- (3-chloropyridin-2-yl) -2-fluorophenyl] -1H-benzimidazole compound Similar to (3) of Example 1 above By the method, 6-tert-butyl-2- [4- (3-chloropyridin-2-yl) -2-fluorophenyl] -1H-benzimidazole compound (yield 91%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.62 (d, 1H), 8.05 (dd, 1H), 8.03 (d, 1H), 7.74-7.70 (m, 2H), 7.66 (s, 1H), 7.47-7.43 (m, 2H)

Examples 68 and 69
In the same manner as in Example 27 (2), compounds 68 and 69 were obtained.

Example 70. Preparation of 6-tert-butyl-2- [4- (3,5-dichloropyridin-2-yl) -2-fluorophenyl] -1H-benzimidazole compound

(1) Production of 4- (3,5-dichloropyridin-2-yl) -2-fluorobenzoic acid compound The same procedure as in Example 1 (1) was carried out to prepare 4- (3,5-dichloro Pyridin-2-yl) -2-fluorobenzoic acid compound (yield 69%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.55 (s, 1H), 8.07 (s, 1H), 7.93 (dd, 1H), 7.59-7.52 (m, 2H)

(2) Preparation of 6-tert-butyl-2- [4- (3,5-dichloropyridin-2-yl) -2-fluorophenyl] -1H-benzimidazole compound (3) of Example 1 above In the same manner, 6-tert-butyl-2- [4- (3,5-dichloropyridin-2-yl) -2-fluorophenyl] -1H-benzimidazole compound (yield 88%) was obtained. .
¹ H NMR (CD ₃ OD) δ: 8.64 (s, 1H), 8.27 (d, 1H), 8.16 (s, 1H), 77.72-7.68 (m, 3H), 7.60 (d, 1H), 7.45 (d , 1H), 1.42 (s, 9H)

Examples 71 and 72
In the same manner as in Example 70 (2), compounds 71 and 72 were obtained.

Example 73. Preparation of 4-chloro-2- [4- (3-chloro-5-trifluoromethylpyridin-2-yl) -2-fluorophenyl] -6-trifluoromethyl-1H-benzimidazole compound

(1) Production of 4- (3-chloro-5-trifluoromethylpyridin-2-yl) -2-fluorobenzoic acid compound The same procedure as in Example 1 (1) was carried out to prepare 4- (3 -Chloro-5-trifluoromethylpyridin-2-yl) -2-fluorobenzoic acid compound (yield 72%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.85 (d, 1H), 8.31 (d, 1H), 7.98 (dd, 1H), 7.60-7.51 (m, 2H)

(2) Preparation of 4-chloro-2- [4- (3-chloro-5-trifluoromethylpyridin-2-yl) -2-fluorophenyl] -6-trifluoromethyl-1H-benzimidazole compound 4-Chloro-2- [4- (3-chloro-5-trifluoromethylpyridin-2-yl) -2-fluorophenyl] -6-trifluoro was prepared in the same manner as in Example 1, (3). A methyl-1H-benzimidazole compound (yield 81%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.96 (s, 1H), 8.42 (s, 2H), 7.92 (s, 1H), 7.88-7.82 (m, 2H), 7.62 (s, 1H)

Examples 74 and 75
In the same manner as in Example 73 (2), compounds 74 and 75 were obtained.

Example 76. Preparation of N- [3,3'-difluoro-4 '-(6-methoxy-1H-benzimidazol-2-yl) biphenyl-4-yl] methanesulfonamide compound

(1) Preparation of 4- (3-fluoro-4-methanesulfonylaminophenyl) -2-fluorobenzoic acid compound 4- (3-Fluoro-4 is carried out in the same manner as (1) in Example 1 above. -Methanesulfonylaminophenyl) -2-fluorobenzoic acid compound (yield 52%) was obtained.
¹ H NMR (CD ₃ OD) δ: 7.94-7.91 (m, 1H), 7.56-7.52 (m, 2H), 7.49-7.41 (m, 3H), 2.98 (s, 3H)

(2) Production of N- [3,3′-difluoro-4 ′-(6-methoxy-1H-benzimidazol-2-yl) biphenyl-4-yl] methanesulfonamide compound (3 of Example 1 above) ) N- [3,3′-difluoro-4 ′-(6-methoxy-1H-benzoimidazol-2-yl) biphenyl-4-yl] methanesulfonamide compound (yield 55%) )
¹ H NMR (CD ₃ OD) δ: 7.73 (d, 1H), 7.71 (d, 1H), 7.58 (s, 1H), 7.55-7.52 (m, 3H), 7.50-7.48 (m, 1H), 7.28 -7.25 (m, 1H), 6.85 (d, 1H), 3.86 (s, 3H), 2.99 (s, 3H)

Example 77. Preparation of 2- [2-fluoro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound

(1) Preparation of 2-fluoro-4- (3-trifluoromethylpyridin-2-yl) benzoic acid compound The same procedure as in (1) of Example 1 was performed to prepare 2-fluoro-4- (3 -Trifluoromethylpyridin-2-yl) benzoic acid compound (yield 71%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.85 (d, 1H), 8.30 (d, 1H), 8.00 (dd, 1H), 7.68 (dd, 1H), 7.38-7.31 (m, 2H)

(2) Preparation of 2- [2-fluoro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound (3) of Example 1 above In the same manner, 2- [2-fluoro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound (yield 83%) was obtained. .
¹ H NMR (CD ₃ OD) δ: 8.89 (d, 1H), 8.36-8.32 (m, 2H), 8.00 (s, 1H), 7.83 (d, 1H), 7.72-7.68 (m, 1H), 7.60 (d, 1H), 7.55 (s, 1H), 7.52 (d, 1H)

Examples 78-80
In the same manner as in Example 77 (2), compounds 78 to 80 were obtained.

Example 81. Preparation of 2- (2-fluoro-4-pyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound

(1) Production of 2-fluoro-4-pyridin-2-ylbenzoic acid compound 2-fluoro-4-pyridin-2-ylbenzoic acid compound (1) was prepared in the same manner as in Example 1 (1). Yield 69%).
¹ H NMR (CD ₃ OD) δ: 7.79-7.74 (m, 2H), 7.46-7.34 (m, 3H), 7.11-7.02 (m, 2H)

(2) Production of 2- (2-fluoro-4-pyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound The same procedure as in (3) of Example 1 was performed. 2- (2-Fluoro-4-pyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound (yield 82%) was obtained.
¹ H NMR (CDCl ₃ ) δ: 8.77-8.71 (m, 1H), 8.06-7.90 (m, 3H), 7.89-7.83 (m, 2H), 7.62-7.51 (m, 4H)

Examples 82-84
In the same manner as in Example 81 (2), compounds 82 to 84 were obtained.

Example 85. Preparation of 2- [2-chloro-4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound

(1) Production of 2-chloro-4- (3-chloropyridin-2-yl) benzoic acid compound 2-chloro-4- (3-chloro) was prepared in the same manner as in Example 1 (1). Pyridin-2-yl) benzoic acid compound (yield 80%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.60-8.58 (m, 1H), 8.02 (dd, 1H), 7.95 (d, 1H), 7.79 (d, 1H), 7.69 (dd, 1H), 7.48-7.44 (m, 1H)

(2) Production of 2- [2-chloro-4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound Similar to (3) of Example 1 above 2- [2-Chloro-4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound (yield 91%) was obtained by the method.
¹ H NMR (CD ₃ OD) δ: 8.63 (d, 1H), 8.05-7.98 (m, 3H), 7.95 (s, 1H), 7.85 (d, 1H), 7.82 (s, 1H), 7.60 (d , 1H), 7.48-7.44 (m, 1H)

Examples 86 and 87
In the same manner as in Example 85 (2), compounds 86 and 87 were obtained.

Example 88. Preparation of 2- [2-chloro-4- (3,5-dichloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound

(1) Production of 2-chloro-4- (3,5-dichloropyridin-2-yl) benzoic acid compound The same procedure as in Example 1 (1) was carried out to prepare 2-chloro-4- (3 , 5-dichloropyridin-2-yl) benzoic acid compound (yield 72%).
¹ H NMR (CD ₃ OD) δ: 8.62 (d, 1H), 8.15 (d, 1H), 7.93 (d, 1H), 7.82 (d, 1H), 7.72 (dd, 1H)

(2) Preparation of 2- [2-chloro-4- (3,5-dichloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound (3) of Example 1 above 2- [2-Chloro-4- (3,5-dichloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound (yield 88%) was obtained in the same manner. .
¹ H NMR (CD ₃ OD) δ: 8.63 (d, 1H), 8.16 (d, 1H), 8.03-7.95 (m, 3H), 7.87-7.82 (m, 2H), 7.59 (d, 1H)

Examples 89-91
In the same manner as in Example 88 (2), compounds 89 to 91 were obtained.

Example 92. Preparation of 2- [2-chloro-4- (3-chloro-5-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound

(1) Production of 2-chloro-4- (3-chloro-5-trifluoromethylpyridin-2-yl) benzoic acid compound Performed in the same manner as in Example 1 (1) above, 2-chloro- 4- (3-Chloro-5-trifluoromethylpyridin-2-yl) benzoic acid compound (yield 68%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.92 (d, 1H), 8.38 (d, 1H), 7.96 (d, 1H), 7.87 (d, 1H), 7.77 (dd, 1H)

(2) Preparation of 2- [2-chloro-4- (3-chloro-5-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound 2- [2-Chloro-4- (3-chloro-5-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound (3) Yield 88%).
¹ H NMR (CDCl ₃ ) δ: 8.85 (s, 1H), 8.37 (d, 1H), 8.08 (s, 1H), 8.01 (s, 1H), 7.94 (s, 1H), 7.88 (d, 1H) , 7.78 (d, 1H), 7.56 (d, 1H)

Example 93. Preparation of 4-chloro-2- [2-chloro-4- (3-chloro-5-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound

4-Chloro-2- [2-chloro-4- (3-chloro-5-trifluoromethylpyridin-2-yl) phenyl] -6--6 is prepared in the same manner as in Example 92 (2) above. A trifluoromethyl-1H-benzimidazole compound (yield 71%) was obtained.
¹ H NMR (CDCl ₃ ) δ: 8.89 (s, 1H), 8.72 (d, 1H), 8.10 (s, 1H), 7.94-7.87 (m, 3H), 7.64 (s, 1H)

Example 94. Preparation of N- [4 '-(6-tert-butyl-1H-benzimidazol-2-yl) -3'-chloro-3-fluorobiphenyl-4-yl] methanesulfonamide compound

(1) Preparation of 4- (3-fluoro-4-methanesulfonylaminophenyl) -2-chlorobenzoic acid compound 4- (3-Fluoro-4 is carried out in the same manner as (1) in Example 1 above. -Methanesulfonylaminophenyl) -2-chlorobenzoic acid compound (yield 54%) was obtained.
¹ H NMR (CD ₃ OD) δ: 7.93 (d, 1H), 7.78 (d, 1H), 7.67-7.63 (m, 2H), 7.60-7.53 (m, 2H), 3.05 (s, 3H)

(2) Production of N- [4 ′-(6-tert-butyl-1H-benzimidazol-2-yl) -3′-chloro-3-fluorobiphenyl-4-yl] methanesulfonamide compound N- [4 ′-(6-tert-butyl-1H-benzoimidazol-2-yl) -3′-chloro-3-fluorobiphenyl-4-yl] methane A sulfonamide compound (yield 60%) was obtained.
¹ H NMR (CD ₃ OD) δ: 7.94 (d, 1H), 7.89 (s, 1H), 7.75 (d, 1H), 7.67-7.56 (m, 5H), 7.44 (d, 1H), 3.06 (s , 3H), 1.41 (s, 9H)

Examples 95 and 96
In the same manner as in Example 94 (2), compounds 95 and 96 were obtained.

Example 97. Preparation of 2- [2-chloro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound

(1) Production of 2-chloro-4- (3-trifluoromethylpyridin-2-yl) benzoic acid compound The same procedure as in Example 1 (1) was carried out to give 2-chloro-4- (3 -Trifluoromethylpyridin-2-yl) benzoic acid compound (yield 73%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.78-8.76 (m, 1H), 8.20 (d, 1H), 7.91 (d, 1H), 7.80-7.76 (m, 2H), 7.41-7.39 (m, 1H)

(2) Preparation of 2- [2-chloro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound (3) of Example 1 above In the same manner, 2- [2-chloro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound (yield 92%) was obtained. .
¹ H NMR (CDCl ₃ ) δ: 8.89 (d, 1H), 8.59 (d, 1H), 8.15 (d, 1H), 8.10-7.75 (m, 1H), 7.73 (s, 1H), 7.65-7.50 ( m, 4H)

Examples 98 and 99
In the same manner as in Example 97 (2), compounds 98 and 99 were obtained.

Example 100. Preparation of 6-tert-butyl-2- [2-chloro-4- (3-methylpyridin-2-yl) phenyl] -1H-benzimidazole compound

A compound dissolved in 20 mL of 1,2-dimethoxyethane and 20 mL of distilled water, 0.46 g (3.6 mmol) of 2-chloro-3-methylpyridine, 2.2 g (21.1 mmol) of Na ₂ CO ₃ , 3- Add 0.6 g (3.0 mmol) of chloro-4-carboxylphenylboronic acid and 50 mg of Pd (PPh ₃ ), and stir for 15 hours under heating to reflux. After concentration under reduced pressure, the aqueous layer is washed with ethyl acetate, adjusted to pH 1 with concentrated hydrochloric acid, extracted several times with ethyl acetate, the organic layer is dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in 25 mL of dimethylformamide, 0.5 g (3.0 mmol) of 4-tert-butylbenzene-1,2-diamine, 1.2 mL (6.0 mmol) of diisopropylethylamine and O- (7-azabenzotriazole). -1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (1.3 g, 7.2 mmol) is added and stirred at room temperature for 16 hours. This is concentrated under reduced pressure, dissolved in ethyl acetate, washed with saturated NaHCO ₃ and saturated NaCl, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is dissolved in acetic acid / toluene (15 mL / 1.5 mL), stirred at 75 ° C. for 3 hours, and concentrated under reduced pressure. This is dissolved in ethyl acetate, washed with saturated NaHCO ₃ and saturated NaCl, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (developing solvent: chloroform / methanol = 30/1) and 6-tert-butyl-2- [2-chloro-4- (3-methylpyridin-2-yl) phenyl] 0.77 g (yield 68%) of -1H-benzimidazole compound was obtained.
¹ H NMR (CDCl ₃ ) δ: 8.69 (d, 1H), 8.56-8.52 (m, 1H), 8.06 (s, 1H), 7.73 (s, 1H), 7.53-7.48 (m, 1H), 7.42- 7.39 (m, 1H), 7.31-7.27 (m, 1H), 7.18-7.14 (m, 1H), 6.89 (d, 1H), 2.67 (s, 3H), 1.38 (s, 9H)

Example 101. Preparation of 6-chloro-2- (2-chloro-4-pyridin-2-ylphenyl) -1H-benzimidazole compound

(1) Production of 2-chloro-4-pyridin-2-yl-benzoic acid 2-chloro-4-pyridin-2-ylbenzoic acid compound (1) was prepared in the same manner as in Example 1 (1). Yield 65%).
¹ H NMR (CD ₃ OD) δ: 8.63 (s, 1H), 8.05 (s, 1H), 7.99-7.89 (m, 2H), 7.41-7.39 (m, 2H), 6.65-6.63 (m, 1H)

(2) Preparation of 6-chloro-2- (2-chloro-4-pyridin-2-ylphenyl) -1H-benzimidazole compound 6-chloro was prepared in the same manner as in Example 1 (3). A 2- (2-chloro-4-pyridin-2-ylphenyl) -1H-benzimidazole compound (yield 85%) was obtained.
¹ H NMR (CDCl ₃ ) δ: 8.72 (d, 1H), 8.48 (d, 1H), 8.19 (s, 1H), 8.00 (d, 1H), 7.82-7.68 (m, 2H), 7.62 (s, 1H), 7.59 (d, 1H), 7.31-7.29 (m, 2H)

Examples 102 and 103
In the same manner as in Example 101 (2), compounds 102 and 103 were obtained.

Example 104. Preparation of 2- [4- (3-chloropyridin-2-yl) naphthalen-1-yl] -6-trifluoromethyl-1H-benzimidazole compound

(1) Production of 4-carboxynaphthalene-1-boronic acid compound To 5 mL of 25% aqueous sodium hydroxide, 0.2 g (1.08 mmol) of 4-methylnaphthalene-1-boronic acid is gradually added and dissolved. This container is installed in an ice water tank to maintain ice cooling conditions. To this, a solution prepared by dissolving 0.43 g (2.70 mmol) of potassium permanganate and 5 mL of distilled water is gradually added over 1 hour. After further stirring for 30 minutes, the ice bath is removed and stirred at 40C for 2 hours. The reaction solution is filtered through celite to remove solids. Add 10 mL of ethyl acetate to the filtered solution. A 5.0N hydrochloric acid solution is added thereto to adjust the pH of the aqueous layer to 4.0, and the mixture is stirred for 30 minutes. The ethyl acetate layer is separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in a small amount of methanol and separated by column chromatography (chloroform / methanol = 10: 1) to obtain 0.14 g of 4-carboxynaphthalene-1-boronic acid (yield 58%).
¹ H NMR (CDCl ₃ ) δ: 7.68-7.62 (m, 2H), 7.40-7.34 (m, 4H)

(2) Production of 4- (3-chloropyridin-2-yl) naphthalene-1-carboxylic acid compound The same procedure as in Example 1 (1) was repeated to give 4- (3-chloropyridin-2- Yl) Naphthalene-1-carboxylic acid compound (yield 60%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.97 (d, 1H), 8.63 (dd, 1H), 8.27 (d, 1H), 8.12 (d, 1H), 7.63-7.49 (m, 4H), 7.40 (d , 1H)

(3) Production of 2- [4- (3-chloropyridin-2-yl) naphthalen-1-yl] -6-trifluoromethyl-1H-benzimidazole compound Similar to (3) of Example 1 above The 2- [4- (3-chloropyridin-2-yl) naphthalen-1-yl] -6-trifluoromethyl-1H-benzimidazole compound (yield 79%) was obtained by the method.
¹ H NMR (CDCl ₃ ) δ: 8.74 (d, 1H), 8.56 (d, 1H), 8.01-7.95 (m, 2H), 7.86 (d, 1H), 7.78 (d, 1H), 7.53 (d, 1H), 7.47 (d, 2H), 7.40-7.27 (m, 3H)

Examples 105-107
It carried out by the method similar to the said Example 1 (3), and obtained the compounds 105-107.

Example 108. Preparation of 6-tert-butyl-2- [4- (3,5-dichloropyridin-2-yl) naphthalen-1-yl] -1H-benzimidazole compound

(1) Preparation of 4- (3,5-dichloropyridin-2-yl) naphthalene-1-carboxylic acid compound 4- (3,5-dichloro is prepared in the same manner as in Example 1 (1). Pyridin-2-yl) naphthalene-1-carboxylic acid compound (yield 56%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.92 (d, 1H), 8.63 (s, 1H), 8.19 (d, 2H), 7.60-7.55 (m, 1H), 7.49-7.42 (m, 2H), 7.36 (d, 1H)

(2) Preparation of 6-tert-butyl-2- [4- (3,5-dichloropyridin-2-yl) naphthalen-1-yl] -1H-benzimidazole compound (3) of Example 1 above In the same manner, 6-tert-butyl-2- [4- (3,5-dichloropyridin-2-yl) naphthalen-1-yl] -1H-benzimidazole compound (yield 79%) was obtained. .
¹ H NMR (DMSO-d ₆ ) δ: 7.99-7.95 (m, 1H), 7.70-7.64 (m, 1H), 7.45-7.41 (m, 1H), 7.18-7.15 (m, 1H), 6.87-6.46 (m, 7H), 0.57 (s, 9H)

Example 109. Preparation of 2- [4- (3,5-dichloropyridin-2-yl) naphthalen-1-yl] -4,6-bistrifluoromethyl-1H-benzimidazole compound

2- [4- (3,5-dichloropyridin-2-yl) naphthalen-1-yl] -4,6-bistrifluoromethyl-1H-benzoate was prepared in the same manner as in Example 108 (2). An imidazole compound (yield 60%) was obtained.
¹ H NMR (DMSO-d ₆ ) δ: 8.00 (d, 1H), 7.68 (s, 1H), 7.50 (d, 1H), 7.44-7.40 (m, 1H), 7.29-7.25 (m, 1H), 6.85-6.63 (m, 5H)

Example 110. Preparation of 6-tert-butyl-2- [4- (3-chloro-5-trifluoromethylpyridin-2-yl) naphthalen-1-yl] -1H-benzimidazole compound

6-tert-Butyl-2- [4- (3-chloro-5-trifluoromethylpyridin-2-yl) naphthalen-1-yl] -1H-benzimidazole was prepared in the same manner as in Example 100 above. A compound (yield 56%) was obtained.
¹ H NMR (DMSO-d ₆ ) δ: 8.36-8.30 (m, 1H), 7.93-7.89 (m, 1H), 7.48-7.44 (m, 1H), 7.28-7.25 (m, 1H), 6.91-6.59 (m, 7H), 0.59 (s, 9H)

Example 111. Preparation of 2- [4- (3-chloro-5-trifluoromethylpyridin-2-yl) naphthalen-1-yl] -4,6-bistrifluoromethyl-1H-benzimidazole compound

2- [4- (3-Chloro-5-trifluoromethylpyridin-2-yl) naphthalen-1-yl] -4,6-bistrifluoromethyl-1H- was prepared in the same manner as in Example 110 above. A benzimidazole compound (yield 55%) was obtained.
¹ H NMR (DMSO-d ₆ ) δ: 8.34 (d, 1H), 7.91 (s, 1H), 7.55 (d, 1H), 7.43-7.37 (m, 1H), 7.27 (d, 1H), 6.84- 6.64 (m, 5H)

Example 112. Production of N- {4- [4- (4,6-bistrifluoromethyl-1H-benzimidazol-2-yl) naphthalen-1-yl] -2-fluorophenyl} methanesulfonamide compound

(1) Production of 4- (3-fluoro-4-methanesulfonylaminophenyl) naphthalene-1-carboxylic acid compound The same method as in (1) of Example 1 above was carried out to give 4- (3-fluoro-4 -Methanesulfonylaminophenyl) naphthalene-1-carboxylic acid compound (yield 43%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.92 (d, 1H), 8.14 (d, 1H), 7.82 (s, 1H), 7.64-7.58 (m, 2H), 7.48-7.41 (m, 2H), 7.29 -7.25 (m, 2H), 3.06 (s, 3H)

(2) Production of N- {4- [4- (4,6-bistrifluoromethyl-1H-benzimidazol-2-yl) naphthalen-1-yl] -2-fluorophenyl} methanesulfonamide compound N- {4- [4- (4,6-bistrifluoromethyl-1H-benzoimidazol-2-yl) naphthalen-1-yl] -2-fluorophenyl was prepared in the same manner as in Example 1, (3). } A methanesulfonamide compound (yield 55%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.43 (d, 1H), 8.00-7.89 (m, 3H), 7.70-7.60 (m, 3H), 7.61-7.52 (m, 2H), 7.37-7.30 (m, 2H), 3.11 (s, 3H)

Example 113. Preparation of 6-trifluoromethyl-2- [4- (3-trifluoromethylpyridin-2-yl) naphthalen-1-yl] -1H-benzimidazole compound

(1) Preparation of 4- (3-trifluoromethylpyridin-2-yl) naphthalene-1-carboxylic acid compound 4- (3-trifluoromethyl) was prepared in the same manner as in Example 1 (1). Pyridin-2-yl) naphthalene-1-carboxylic acid compound (yield 60%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.75 (d, 1H), 8.35 (d, 1H), 8.26 (d, 2H), 7.74-7.70 (m, 2H), 7.59-7.54 (m, 2H), 7.25 (d, 1H)

(2) Preparation of 6-trifluoromethyl-2- [4- (3-trifluoromethylpyridin-2-yl) naphthalen-1-yl] -1H-benzimidazole compound (3) of Example 1 above In the same manner, 6-trifluoromethyl-2- [4- (3-trifluoromethylpyridin-2-yl) naphthalen-1-yl] -1H-benzimidazole compound (yield 64%) was obtained. .
¹ H NMR (CDCl ₃ ) δ: 8.60-8.50 (m, 3H), 8.13-8.11 (m, 1H), 7.91-7.85 (m, 1H), 7.65-7.62 (m, 1H), 7.47-7.42 (m , 2H), 7.34-7.30 (m, 2H), 7.49-7.46 (m, 1H), 7.02-6.98 (m, 1H)

Example 114. Preparation of 6-tert-butyl-2- (4-pyridin-2-ylnaphthalen-1-yl) -1H-benzimidazole compound

In the same manner as in Example 100, 6-tert-butyl-2- (4-pyridin-2-ylnaphthalen-1-yl) -1H-benzimidazole compound (yield 57%) was obtained.
¹ H NMR (CDCl ₃ ) δ: 8.74 (d, 1H), 7.98 (d, 1H), 7.88 (d, 1H), 7.78 (d, 2H), 7.60 (d, 2H), 7.52-7.40 (m, 6H), 1.48 (s, 9H)

Example 115. Preparation of 2- (4-pyridin-2-ylnaphthalen-1-yl) -4,6-bistrifluoromethyl-1H-benzimidazole compound

In the same manner as in Example 114, 2- (4-pyridin-2-ylnaphthalen-1-yl) -4,6-bistrifluoromethyl-1H-benzimidazole compound (yield 47%) was obtained. It was.
¹ H NMR (CD ₃ OD) δ: 8.74 (d, 1H), 8.44 (d, 1H), 8.03 (d, 2H), 7.94 (d, 2H), 7.72-7.66 (m, 3H), 7.64-7.58 (m, 2H), 7.05 (d, 1H)

Example 116. Preparation of 6-tert-butyl-2- [3-chloro-4- (3-chloropyridin-2-yl) phenyl] -1H-benzimidazole compound

(1) Production of 3-chloro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzoic acid compound Similar to (1) of Example 104 above To obtain 3-chloro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzoic acid compound (yield 50%).
¹ H NMR (CD ₃ OD) δ: 7.89 (s, 1H), 7.80 (d, 1H), 7.65 (d, 1H), 1.37 (s, 12H)

(2) Production of 3-chloro-4- (3-chloropyridin-2-yl) benzoic acid compound 3-chloro-4- (3-chloro is prepared in the same manner as in Example 1 (1). Pyridin-2-yl) benzoic acid compound (yield 69%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.51 (dd, 1H), 8.04 (d, 1H), 7.97 (dd, 1H), 7.95 (dd, 1H), 7.45 (dd, 1H), 7.32 (d, 1H )

(3) Production of 6-tert-butyl-2- [3-chloro-4- (3-chloropyridin-2-yl) phenyl] -1H-benzimidazole compound Similar to (3) of Example 1 above By the method, 6-tert-butyl-2- [3-chloro-4- (3-chloropyridin-2-yl) phenyl] -1H-benzimidazole compound (yield 86%) was obtained.
¹ H NMR (CDCl ₃ ) δ: 8.72 (d, 1H), 8.48 (d, 1H), 8.19 (s, 1H), 8.00 (d, 1H), 7.82-7.68 (m, 1H), 7.62 (s, 1H), 7.59 (d, 1H), 7.31-7.29 (m, 2H), 1.42 (s, 9H)

Example 117. Preparation of 2- [3-chloro-4- (3,5-dichloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound

(1) Production of 3-chloro-4- (3,5-dichloropyridin-2-yl) benzoic acid compound The same procedure as in Example 1 (1) was carried out to prepare 3-chloro-4- (3 , 5-dichloropyridin-2-yl) benzoic acid compound (yield 64%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.58 (s, 1H), 8.13 (s, 1H), 8.10 (d, 1H), 8.00 (d, 1H), 7.36 (d, 1H)

(2) Preparation of 2- [3-chloro-4- (3,5-dichloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound (3) of Example 1 above In the same manner, 2- [3-chloro-4- (3,5-dichloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound (yield 70%) was obtained. .
¹ H NMR (CD ₃ OD) δ: 8.56 (s, 1H), 8.26 (s, 1H), 8.12 (dd, 2H), 7.88 (s, 1H), 7.72 (d, 1H), 7.54 (d, 1H ), 7.49 (d, 1H)

Examples 118 and 119
In the same manner as in Example 117 (2), compounds 118 and 119 were obtained.

Example 120. Preparation of 2- [3-chloro-4- (3-chloro-5-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound

(1) Production of 3-chloro-4- (3-chloro-5-trifluoromethylpyridin-2-yl) benzoic acid compound The same procedure as in Example 1 (1) was carried out to prepare 3-chloro- 4- (3-Chloro-5-trifluoromethylpyridin-2-yl) benzoic acid compound (yield 69%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.90 (s, 1H), 8.39 (s, 1H), 8.11 (s, 1H), 8.00 (d, 1H), 7.33 (d, 1H)

(2) Preparation of 2- [3-chloro-4- (3-chloro-5-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound 2- [3-Chloro-4- (3-chloro-5-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound (3) Yield 80%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.60 (s, 1H), 8.09 (s, 1H), 7.99-7.96 (m, 1H), 7.85 (s, 1H), 7.69 (d, 1H), 7.53-7.48 (m, 3H)

Examples 121 and 122
In the same manner as in Example 120 (2), compounds 121 and 122 were obtained.

Example 123. Preparation of N- [2'-chloro-4 '-(4-chloro-6-trifluoromethyl-1H-benzimidazol-2-yl) -3-fluorobiphenyl-4-yl] methanesulfonamide compound

(1) Production of 3-chloro-4- (3-fluoro-4-methanesulfonylaminophenyl) benzoic acid compound The same procedure as in (1) of Example 1 was carried out to prepare 3-chloro-4- (3 -Fluoro-4-methanesulfonylaminophenyl) benzoic acid compound (yield 54%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.06 (s, 1H), 7.92 (d, 1H), 7.58 (dd, 1H), 7.40 (d, 1H), 7.34 (s, 1H), 7.28-7.25 (m , 1H), 3.06 (s, 3H)

(2) Production of N- [2′-chloro-4 ′-(4-chloro-6-trifluoromethyl-1H-benzimidazol-2-yl) -3-fluorobiphenyl-4-yl] methanesulfonamide compound N- [2′-chloro-4 ′-(4-chloro-6-trifluoromethyl-1H-benzimidazol-2-yl) -3-3 was prepared in the same manner as in Example 1 (3). Fluorobiphenyl-4-yl] methanesulfonamide compound (yield 60%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.40 (s, 1H), 8.21 (d, 1H), 7.88 (s, 1H), 7.42-7.34 (m, 3H), 7.42-7.34 (m, 2H), 3.08 (s, 3H)

Example 124. Preparation of N- [4 '-(4,6-bistrifluoromethyl-1H-benzimidazol-2-yl) -2'-chloro-3-fluorobiphenyl-4-yl] methanesulfonamide compound

N- [4 ′-(4,6-bistrifluoromethyl-1H-benzimidazol-2-yl) -2′-chloro-3-fluorobiphenyl was prepared in the same manner as in Example 123 (2). -4-yl] methanesulfonamide compound (yield 56%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.43 (s, 1H), 8.25 (d, 1H), 8.18 (s, 1H), 7.83 (s, 1H), 7.67-7.61 (m, 2H), 7.43-7.34 (m, 2H), 3.10 (s, 3H)

Example 125. Preparation of 2- (3-chloro-4-pyridin-2-ylphenyl) -6-trifluoromethyl-1H-benzimidazole compound

(1) Production of 3-chloro-4-pyridin-2-ylbenzoic acid compound 3-chloro-4-pyridin-2-ylbenzoic acid compound (1) was prepared in the same manner as in Example 1 (1). Yield 68%).
¹ H NMR (CD ₃ OD) δ: 8.66 (d, 1H), 8.14 (s, 1H), 8.05 (d, 1H), 7.99 (dd, 1H), 7.71 (d, 1H), 7.64 (d, 1H ), 7.48 (dd, 1H)

(2) Production of 2- (3-chloro-4-pyridin-2-ylphenyl) -6-trifluoromethyl-1H-benzimidazole compound 2 was carried out in the same manner as (3) in Example 1 above. -(3-Chloro-4-pyridin-2-ylphenyl) -6-trifluoromethyl-1H-benzimidazole compound (yield 88%) was obtained.
¹ H NMR (DMSO-d ₆ ) δ: 7.93-7.89 (m, 1H), 7.63-7.56 (m, 1H), 7.50-7.44 (m, 1H), 7.19-7.11 (m, 2H), 7.02-6.95 (m, 3H), 6.76 (s, 1H), 6.67-6.62 (m, 1H)

Examples 126-130.
In the same manner as in Example 125 (2), compounds 126 to 130 were obtained.

Example 131. Preparation of 2- [3-chloro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound

(1) Production of 3-chloro-4- (3-trifluoromethylpyridin-2-yl) benzoic acid compound The same procedure as in Example 1 (1) was carried out to prepare 3-chloro-4- (3 -Trifluoromethylpyridin-2-yl) benzoic acid compound (yield 76%) was obtained.
¹ H NMR (CD ₃ OD) δ: 7.98-7.91 (m, 3H), 7.60-7.57 (m, 2H), 7.46 (d, 1H)

(2) Preparation of 2- [3-chloro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound (3) of Example 1 above 2- [3-Chloro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound (yield 89%) was obtained in the same manner. .
¹ H NMR (CDCl ₃ ) δ: 8.02 (s, 1H), 7.97-7.93 (m, 1H), 7.85 (s, 1H), 7.64 (d, 1H), 7.44 (d, 2H), 7.42-7.37 ( m, 3H)

Examples 132-134
In the same manner as in Example 131 (2), compounds 132 to 134 were obtained.

Example 135. Preparation of 2- [3-chloro-4- (3-methylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound

2- [3-Chloro-4- (3-methylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole compound (yield 48%) )
¹ H NMR (CDCl ₃ ) δ: 8.01 (s, 1H), 7.96-7.91 (m, 1H), 7.84 (s, 1H), 7.62 (d, 1H), 7.44 (d, 1H), 7.37-7.34 ( m, 4H), 2.70 (s, 3H)

Example 136. Preparation of 3-chloro-6 '-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3'] bipyridine compound

(1) Production of 3-chloro-2- (6-methylpyridin-3-yl) pyridine compound 0.5 g of 2,3-dichloropyridine dissolved in 20 mL of 1,2-dimethoxyethane and 20 mL of distilled water (3. 6 mmol) was charged with 2.2 g (21.1 mmol) of Na ₂ CO ₃ , 0.41 g (3.0 mmol) of 2-methylpyridine-5-boronic acid and 50 mg of Pd (PPh ₃ ) ₄ and heated under reflux for 18 hours Stir. After cooling to room temperature and concentrating under reduced pressure to approximately 50%, the aqueous layer is washed with ethyl acetate, the organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was separated by column chromatography (developing solvent: ethyl acetate / hexane = 1/10), and 0.56 g of 3-chloro-2- (6-methylpyridin-3-yl) pyridine compound (yield 80%) )
¹ H NMR (CDCl ₃ ) δ: 8.91 (d, 1H), 8.63 (dd, 1H), 7.99 (dd, 1H), 7.83 (dd, 1H), 7.49-7.47 (m, 1H), 7.30-7.27 ( m, 1H), 2.65 (s, 3H)

(2) Preparation of 5- (3-chloropyridin-2-yl) pyridine-2-carboxylic acid compound 5- (3-chloropyridine-2-yl) Yl) pyridine-2-carboxylic acid compound (yield 69%) was obtained.
¹ H NMR (CDCl ₃ ) δ: 9.03 (d, 1H), 8.67 (dd, 1H), 8.36-8.32 (m, 2H), 7.88 (dd, 1H), 7.39-7.34 (m, 1H)

(3) Production of 3-chloro-6 ′-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine compound A method similar to (3) of Example 1 above To give 3-chloro-6 ′-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine compound (yield 92%).
¹ H NMR (CDCl ₃ ) δ: 9.04 (d, 1H), 8.65 (dd, 1H), 8.58 (d, 1H), 8.35 (dd, 1H), 8.00 (s, 1H), 7.88 (dd, 1H) , 7.78 (s, 1H), 7.56 (dd, 1H), 7.32 (dd, 1H)

Examples 137-145
In the same manner as in Example 136 (3), compounds 137 to 145 were obtained.

Example 146. Preparation of 3-chloro-6 '-(6-morpholin-4-yl-1H-benzimidazol-2-yl)-[2,3'] bipyridine compound

3-Chloro-6 ′-(6-morpholin-4-yl-1H-benzoimidazol-2-yl)-[2,3 ′] bipyridine compound (yield 72) was prepared in the same manner as in Example 17 above. %).
¹ H NMR (CD ₃ OD) δ: 9.21 (dd, 1H), 8.69 (d, 1H), 8.48 (dd, 1H), 8.35 (d, 1H), 8.09 (d, 1H), 7.73 (d, 1H ), 7.55-7.50 (m, 1H), 7.45 (dd, 1H), 7.23 (d, 1H), 3.92-3.88 (m, 4H), 3.32-3.29 (m, 4H)

Examples 147-150
In the same manner as in Example 146, compounds 147 to 150 were obtained.

Example 151. Preparation of 3,5-dichloro-6 '-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3'] bipyridine compound

(1) Production of 3,5-dichloro-2- (6-methylpyridin-3-yl) pyridine compound The same procedure as in Example 136 (1) was repeated, followed by 3,5-dichloro-2- ( 6-methylpyridin-3-yl) pyridine compound (yield 72%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.76 (s, 1H), 8.67 (s, 1H), 8.20-8.11 (m, 2H), 7.47-7.43 (m, 1H), 2.61 (s, 3H)

(2) 3,5-dichloro-6 ′-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine compound (in the same manner as in Example 100) Yield 65%).
¹ H NMR (CDCl ₃ ) δ: 9.05 (s, 1H), 8.81 (d, 1H), 8.62 (s, 1H), 8.37 (d, 1H), 8.10 (s, 1H), 7.90 (s, 1H) , 7.86 (d, 1H), 7.64 (d, 1H)

Examples 152-155
In the same manner as in Example 151 (2), compounds 152 to 155 were obtained.

Example 156. Preparation of 6 '-(4,6-bistrifluoromethyl-1H-benzimidazol-2-yl) -3-chloro-5-trifluoromethyl- [2,3'] bipyridine compound

(1) Preparation of 3-chloro-5-trifluoromethyl-2- (6-methylpyridin-3-yl) pyridine compound 3-chloro-5 was prepared in the same manner as in Example 136 (1). -Trifluoromethyl-2- (6-methylpyridin-3-yl) pyridine compound (yield 79%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.94 (s, 1H), 8.82 (s, 1H), 8.39 (s, 1H), 8.16 (d, 1H), 7.48 (d, 1H), 2.63 (s, 3H )

(2) Preparation of 5- (3-chloro-5-trifluoromethylpyridin-2-yl) pyridine-2-carboxylic acid compound The same procedure as in Example 104 (1) above was carried out to give 5- (3 -Chloro-5-trifluoromethylpyridin-2-yl) pyridine-2-carboxylic acid compound (yield 70%) was obtained.
¹ H NMR (CD ₃ OD) δ: 9.05-8.95 (m, 2H), 8.42-8.38 (m, 2H), 7.66-7.62 (m, 1H)

(3) Preparation of 6 ′-(4,6-bistrifluoromethyl-1H-benzimidazol-2-yl) -3-chloro-5-trifluoromethyl- [2,3 ′] bipyridine compound Example 1 above 6 ′-(4,6-bistrifluoromethyl-1H-benzoimidazol-2-yl) -3-chloro-5-trifluoromethyl- [2,3 ′] bipyridine was prepared in the same manner as in (3) above. A compound (yield 73%) was obtained.
¹ H NMR (CDCl ₃ ) δ: 9.15 (s, 1H), 8.93 (s, 1H), 8.56 (d, 1H), 8.39-8.33 (m, 2H), 8.13 (s, 1H), 7.85 (s, 1H)

Example 157. Preparation of 6 '-(6-methoxy-1H-benzimidazol-2-yl) -3-chloro-5-trifluoromethyl- [2,3'] bipyridine compound

6 ′-(6-Methoxy-1H-benzoimidazol-2-yl) -3-chloro-5-trifluoromethyl- [2,3 ′] was prepared in the same manner as in Example 156 (3) above. A bipyridine compound (yield 91%) was obtained.
¹ H NMR (CDCl ₃ ) δ: 8.91 (s, 1H), 8.25-8.20 (m, 1H), 8.12 (s, 1H), 7.57 (d, 1H), 7.36 (s, 1H), 7.36-7.28 ( m, 3H), 3.94 (s, 3H)

Example 158. Preparation of 3-trifluoromethyl-6 '-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3'] bipyridine compound

(1) Production of 3-trifluoromethyl-2- (6-methylpyridin-3-yl) pyridine compound The same procedure as in Example 136 (1) was repeated to give 3-trifluoromethyl-2- ( 6-methylpyridin-3-yl) pyridine compound (yield 82%) was obtained.
¹ H NMR (CDCl ₃ ) δ: 8.88 (d, 1H), 8.67 (s, 1H), 8.12 (dd, 1H), 7.76 (dd, 1H), 7.54-7.49 (m, 1H), 7.29-7.28 ( m, 1H), 2.66 (s, 3H)

(2) Preparation of 5- (3-trifluoromethylpyridin-2-yl) pyridin-2-ylcarboxylic acid compound 5- (3-trifluoromethyl) was prepared in the same manner as in Example 104 (1). Pyridin-2-yl) pyridin-2-ylcarboxylic acid compound (yield 75%) was obtained.
¹ H NMR (CD ₃ OD) δ: 8.92-8.89 (m, 1H), 8.79 (s, 1H), 8.34-8.27 (m, 2H), 8.15 (s, 1H), 7.73-7.68 (m, 1H)

(3) Production of 3-trifluoromethyl-6 ′-(6-trifluoromethyl-1H-benzoimidazol-2-yl)-[2,3 ′] bipyridine compound Same as (3) of Example 1 above To obtain 3-trifluoromethyl-6 ′-(6-trifluoromethyl-1H-benzoimidazol-2-yl)-[2,3 ′] bipyridine compound (yield 94%).
¹ H NMR (CDCl ₃ ) δ: 8.94 (d, 1H), 8.84 (s, 1H), 8.61 (d, 1H), 8.19 (d, 1H), 8.11 (d, 1H), 8.10 (s, 1H) , 8.08 (d, 1H), 7.61-7.54 (m, 2H)

Examples 159-168
In the same manner as in Example 158 (3), compounds 159 to 168 were obtained.

Example 169. Preparation of 6 '-(6-morpholin-4-yl-1H-benzimidazol-2-yl) -3-trifluoromethyl- [2,3'] bipyridine compound

The 6 '-(6-morpholin-4-yl-1H-benzimidazol-2-yl) -3-trifluoromethyl- [2,3'] bipyridine compound (yield) was prepared in the same manner as in Example 17 above. Rate 67%).
¹ H NMR (CD ₃ OD) δ: 8.90 (d, 1H), 8.80 (s, 1H), 8.33 (dd, 1H), 8.27 (dd, 1H), 8.07 (dd, 1H), 7.75-7.81 (br , 1H), 7.66 (dd, 1H), 7.65-7.55 (br, 1H), 7.41 (dd, 1H), 3.88-3.92 (m, 4H), 3.32-3.29 (m, 4H)

Example 170. Preparation of 6 '-(4-morpholin-4-yl-6-trifluoromethyl-1H-benzimidazol-2-yl) -3-trifluoromethyl- [2,3'] bipyridine compound

6 ′-(4-morpholin-4-yl-6-trifluoromethyl-1H-benzimidazol-2-yl) -3-trifluoromethyl- [2,3] was prepared in the same manner as in Example 169 above. '] A bipyridine compound (yield 67%) was obtained.
¹ H NMR (CDCl ₃ ) δ: 10.94 (s, 1H), 8.92 (d, 1H), 8.79 (s, 1H), 8.53 (d, 1H), 8.15 (d, 1H), 8.06 (dd, 1H) , 7.56-7.52 (m, 1H), 7.09 (s, 1H), 6.82 (s, 1H), 4.06-4.00 (m, 4H), 3.72-3.67 (m, 4H)

Example 171. Preparation of 6 '-(6-chloro-1H-benzimidazol-2-yl)-[2,3'] bipyridine compound

(1) Production of 2- (6-methylpyridin-3-yl) pyridine compound A 2- (6-methylpyridin-3-yl) pyridine compound (1) was prepared in the same manner as in Example 136 (1). Yield 67%).
¹ H NMR (CDCl ₃ ) δ: 9.08 (d, 1H), 8.72 (dd, 1H), 8.24 (dd, 1H), 7.79-7.75 (m, 2H), 7.62-7.45 (m, 1H), 7.30- 7.27 (m, 1H), 2.64 (s, 3H)

(2) Production of 5- (pyridin-2-yl) pyridine-2-carboxylic acid compound 5- (pyridin-2-yl) pyridin-2- A carboxylic acid compound (yield 77%) was obtained.
¹ H NMR (CD ₃ OD) δ: 9.30 (s, 1H), 8.73 (d, 1H), 8.62 (d, 1H), 8.30 (d, 1H), 8.07-7.98 (m, 2H), 7.49 (d , 1H)

(3) Production of 6 ′-(6-chloro-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine compound 6′- was carried out in the same manner as in (3) of Example 1 above. (6-Chloro-1H-benzoimidazol-2-yl)-[2,3 ′] bipyridine compound (yield 90%) was obtained.
¹ H NMR (CDCl ₃ ) δ: 7.80-7.78 (m, 1H), 7.70-7.67 (m, 1H), 7.62-7.58 (m, 1H), 7.46-7.45 (m, 1H), 7.32-7.13 (m , 6H)

Examples 172 and 173
In the same manner as in Example 171 (3), compounds 172 and 173 were obtained.

Example 174. Preparation of 6-tert-butyl-2- (6-naphthalen-1-ylpyridin-3-yl) -1H-benzimidazole compound

In the same manner as in Example 100, 6-tert-butyl-2- (6-naphthalen-1-ylpyridin-3-yl) -1H-benzimidazole compound (yield 53%) was obtained.
¹ H NMR (CD ₃ OD) δ: 9.40 (s, 1H), 8.62 (d, 1H), 8.00-7.95 (m, 5H), 7.58-7.46 (m, 6H), 1.28 (s, 9H)

Examples 175-177
In the same manner as in Example 174, compounds 175 to 177 were obtained.

Example 178. Preparation of 2- (4-pyrrol-1-ylphenyl] -6-trifluoromethyl-1H-benzimidazole compound

In the same manner as in Example 1 (3), 2- (4-pyrrol-1-ylphenyl) -6-trifluoromethyl-1H-benzimidazole compound (yield 77%) was obtained.
¹ H NMR (CDCl ₃ ) δ: 8.12 (d, 2H, J = 8.7 Hz), 7.92 (s, 1H), 7.69 (d, 1H, J = 8.6 Hz), 7.54-7.49 (m, 3H), 7.15 -7.14 (m, 2H), 6.40-6.38 (m, 2H)

Examples 179-200
In the same manner as in Example 178, compounds 179 to 200 were obtained.

Example 201. Preparation of 2- [4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole hydrochloride 2- [4- (3-chloropyridin-2-yl) phenyl] Dissolve 500 mg (1.34 mmol) of -6-trifluoromethyl-1H-benzimidazole in 10 mL of diethyl ether and stir for 30 minutes under freezing. This is saturated with gaseous hydrochloric acid and stirred for 1 hour below freezing. The resulting white precipitate was filtered and dried under vacuum for 24 hours to give 2- [4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole hydrochloride 513 mg was obtained.
¹ H NMR (CD ₃ OD) δ: 8.75 (d, 1H), 8.38 (d, 2H), 8.29 (d, 1H), 8.23 (s, 1H), 8.13 (d, 2H), 8.10 (d, 1H ), 7.97 (d, 1H), 7.70 (dd, 1H)
mp: 291-293 ° C

Example 202. Preparation of 6-tert-butyl-2- [4- (3-chloropyridin-2-yl) phenyl] -1H-benzimidazole hydrochloride compound The 6-tert-butyl was prepared in the same manner as in Example 201 above. 500 mg of -2- [4- (3-chloropyridin-2-yl) phenyl] -1H-benzimidazole hydrochloride was obtained.
¹ H NMR (CD ₃ OD) δ: 8.73 (d, 1H), 8.30 (d, 2H), 8.26 (d, 1H), 8.10 (d, 2H), 7.83 (d, 2H), 7.81 (s, 1H ), 7.67 (dd, 1H), 1.47 (s, 9H)
mp: 189-190 ° C

Example 203. Preparation of 6-tert-butyl-2- [4- (3-chloropyridin-2-yl) naphthalen-1-yl] -1H-benzimidazole hydrochloride 6 -Tert-Butyl-2- [4- (3-chloropyridin-2-yl) naphthalen-1-yl] -1H-benzimidazole hydrochloride 510 mg was obtained.
¹ H NMR (CD ₃ OD) δ: 8.68 (d, 1H), 8.20 (d, 1H), 8.16-8.11 (m, 2H), 7.83-7.72 (m, 5H), 7.66-7.62 (m, 2H) , 7.54 (d, 1H), 1.41 (s, 9H)
mp: 208-214 ° C

Example 204. Production of 6 ′-(4,6-bistrifluoromethyl-1H-benzimidazol-2-yl) -3-chloro [2,3 ′] bipyridine hydrochloride compound 520 mg of '-(4,6-bistrifluoromethyl-1H-benzimidazol-2-yl) -3-chloro [2,3 ′] bipyridine hydrochloride was obtained.
¹ H NMR (CD ₃ OD) δ: 9.03 (s, 1H), 8.61-8.53 (m, 2H), 8.30 (d, 1H), 8.15 (s, 1H), 8.03 (d, 1H), 7.77 (s , 1H), 7.47-7.43 (m, 1H)
mp: 133-135 ° C

Example 205. Preparation of 3-trifluoromethyl-6 ′-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine hydrochloride compound The same procedure as in Example 201 was performed. 495 mg of 3-trifluoromethyl-6 ′-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine hydrochloride was obtained.
¹ H NMR (CD ₃ OD) δ: 9.00 (s, 1H), 8.91 (d, 1H), 8.46 (d, 1H), 8.35-8.28 (m, 2H), 8.17 (s, 1H), 8.04 (d , 1H), 7.90 (d, 1H), 7.73-7.69 (m, 1H)
mp: 234-240 ° C

Example 206. Preparation of 6-tert-butyl-2- [4- (3-chloropyridin-2-yl) phenyl] -1H-benzimidazole sodium salt compound 6-tert-butyl-2- [4- (3-chloropyridine- 2-yl) phenyl] -1H-benzimidazole (100 mg, 0.28 mmol) was dissolved in 2.8 mL of 0.1N sodium hydroxide and 0.5 mL of methanol, stirred at room temperature for 30 minutes, concentrated under reduced pressure, and pale yellow As a precipitate, 107 mg of 6-tert-butyl-2- [4- (3-chloropyridin-2-yl) phenyl] -1H-benzimidazole sodium salt was obtained.
¹ H NMR (CD ₃ OD) δ: 8.60 (d, 1H), 8.22 (d, 2H), 8.04 (d, 1H), 7.85 (d, 2H), 7.65 (s, 1H), 7.57 (d, 1H ), 7.48-7.38 (m, 2H), 1.43 (s, 9H)
mp: 317-324 ° C

Example 207. Preparation of 3-trifluoromethyl-6 ′-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine sulfate compound 1.0 g (2.45 mmol) of a pyridine compound was added to acetone. Dissolve in 30 mL and stir for 30 minutes below freezing. To this, 0.16 mL (2.94 mmol) of sulfuric acid diluted in 20 mL of acetone was gradually added dropwise for 10 minutes. After stirring for 1 hour under freezing, the resulting white precipitate was vacuum dried to give 3-trifluoromethyl-6 ′-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 '] Bipyridine sulfate 1.22g was obtained.
¹ H NMR (CD ₃ OD) δ: 9.07 (s, 1H), 8.99 (d, 1H), 8.55 (d, 1H), 8.46 (d, 1H), 8.37 (dd, 1H), 8.26 (s, 1H ), 8.12 (d, 1H), 7.97 (d, 1H), 7.80-7.74 (m, 1H)

Example 208. Preparation of 3-trifluoromethyl-6 ′-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine phosphate compound 1.0 g (2.45 mmol) of a bipyridine compound was prepared. Dissolve in 30 mL of acetone and stir for 30 minutes below freezing. To this, 0.16 mL (2.94 mmol) of phosphoric acid diluted in 20 mL of acetone was gradually added dropwise for 10 minutes. After stirring for 1 hour under freezing, the resulting white precipitate was vacuum dried to give 3-trifluoromethyl-6 ′-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 '] Bipyridine phosphate 1.23g was obtained.
¹ H NMR (CD ₃ OD) δ :: 8.92 (dd, 1H), 8.85 (s, 1H), 8.45 (d, 1H), 8.34 (d, 1H), 8.14 (dd, 1H), 8.00 (s, 1H), 7.83 (d, 1H), 7.72-7.70 (m, 1H), 7.59 (d, 1H)

Example 209. Preparation of 3-trifluoromethyl-6 ′-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridinemethanesulfonate compound 1.0 g (2.45 mmol) of bipyridine compound Is dissolved in 30 mL of diethyl ether and stirred for 30 minutes under ice cooling. To this, 0.19 mL (2.94 mmol) of methanesulfonic acid diluted in 20 mL of diethyl ether was gradually added dropwise for 10 minutes. After stirring for 1 hour under ice-cooling, the resulting white precipitate was vacuum-dried to give 3-trifluoromethyl-6 ′-(6-trifluoromethyl-1H-benzoimidazol-2-yl)-[2, 3 '] Bipyridine methanesulfonate 1.25g was obtained.
¹ H NMR (CD ₃ OD) δ: 9.05 (s, 1H), 8.96 (d, 1H), 8.52 (d, 1H), 8.41-8.32 (m, 2H), 8.24 (s, 1H), 8.10 (d , 1H), 7.95 (d, 1H), 7.76 (dd, 1H), 2.72 (s, 3H)

Example 210. Preparation of 3-trifluoromethyl-6 ′-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridinebenzenesulfonate compound 1.0 g (2.45 mmol) of bipyridine compound Is dissolved in 30 mL of diethyl ether and stirred for 30 minutes under freezing. To this, 0.85 mg (5.39 mmol) of benzenesulfonic acid diluted in 20 mL of diethyl ether was gradually added dropwise for 10 minutes. After stirring for 1 hour under freezing, the resulting white precipitate was vacuum dried to give 3-trifluoromethyl-6 ′-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 '] 1.39 g of bipyridinebenzenesulfonate was obtained.
¹ H NMR (CD ₃ OD) δ: 9.07 (s, 1H), 9.00 (d, 1H), 8.53 (d, 1H), 8.49 (d, 1H), 8.31 (d, 2H), 8.23 (s, 1H ), 8.10 (d, 1H), 7.97 (d, 1H), 7.84-7.80 (m, 6H), 7.44-7.38 (m, 7.5H)

Experimental Example 1 Vanilloid Receptor Inhibitory Efficacy Test 1) Preparation of Test Compound The compound synthesized as in the example was prepared by dissolving in dimethyl sulfoxide (DMSO) to a concentration of 10 mM. The solution prepared in this way was used for the experiment after diluting to a concentration of 1 μM with physiological saline having the same composition as the pipette solution shown in Table 1 for evaluation of the ability to inhibit patch clamp activity.

2) VR1 patch clamp activity inhibition ability evaluation In this experiment, the activity change of VR1 was recorded and measured using an electrophysiological method.
The HEK293 cell line subcultured with rat TRPV1 cDNA was transfected with the gene using lipofectamin and used for experiments.

  HEK293 cells transfected with rat TRPV1 gene were treated with trypsin and separated from the cell culture dish, and then the cells were shaken off in a patch clamp recording chamber and then experimented.

  At this time, the cover glass slip constituting the bottom of the patch clamp recording chamber is treated with a 50% poly-L-lysine solution for 15 minutes or longer so that HEK cells adhere well to the bottom. did. Using an inside-out patch clamp method from an arbitrarily selected HEK cell at room temperature (˜25 ° C.), a cell membrane piece is peeled off, and then capsaicin is 10 μM in the cytoplasmic side. And activated the capsaicin current by VR1. When the capsaicin current was in a stable state, each compound was administered with 10 μM capsaicin, the current suppression effect of the compound was recorded, and the degree of suppression was expressed as a percentage. Since the capsaicin current has the property of being rapidly run-down by calcium ions inside and outside the cell membrane, the ion composition shown in Table 1 is used in order to prevent this and to record the effective inhibitory properties of the compounds. It experimented using the experimental solution which has.

  The experimental results were analyzed by inputting data into a computer after amplifying current using Digidata 1200B A / D converter and Axopatch 1D amplifier of Axon, USA. The inhibitory ability of the compound was expressed as% relative to the capsaicin current value immediately before administration of each compound.

Experimental Example 2. Vanilloid Receptor Calcium Influx Experiment To measure activity as an antagonist, a calcium influx experiment was performed.

1) Cell Culture The hVR1-HEK293 cell line is a cell line in which a human Embryonic Kidney (HEK) 293 Tet-on cell is transfected with a human vanilloid-1 gene (pTRE2hyg-hVR1, 7.8 kb). This is a cell that can regulate the expression of VR1 by administration of deoxycyclin, which is an analog of tetracycline, and is cultured in a medium to which deoxycycline has been added two days ago for a calcium influx experiment. Were used after inducing the expression of VR1. First, hVR1-HEK293 cells cultured to a density of about 80% in a T75 flask were treated with a trypsin solution, dropped into the flask, and centrifuged to collect the cells. This was suspended in a medium supplemented with 1 μg / mL deoxycycline, then diluted to a density of 2-4 × 10 ⁵ cells / mL, and a 100 μL aliquot of cell suspension was added to each well of a 96-well black plate. It was. This was cultured in a 5% CO ₂ cell incubator at 37 ° C. for 2 days and used for the experiment.

2) Preparation of compound sample The compound was dissolved in dimethyl sulfoxide (DMSO) and used for calcium inflow experiments.

3) Measurement of calcium inflow In order to measure the amount of calcium inflow into cells, the cells were cultured at 37 ° C. for 90 minutes in a medium supplemented with calcium indicator Fluo-3 / AM. The fluorescent dye was allowed to permeate, and then washed three times using D-PBS (Dulbecco's phosphate buffered saline) containing 10 mM HEPES to remove the fluorescent dye that did not penetrate into the cells. A 193 μL aliquot of D-PBS was added to each well followed by various concentrations of compound. To measure activity as an antagonist, cells were treated with 1 μM capsaicin to induce calcium influx. The effect of inducing intracellular calcium influx due to the compound concentration with respect to 1 μM capsaicin was measured with a fluorescence analyzer, and the obtained data was substituted into the Hill equation and analyzed.

4) Measurement results

Experimental Example 3. Analgesic Efficacy Experiment In order to evaluate the analgesic efficacy of a newly produced compound, a PBQ-induced writhing experiment using mice was performed. As experimental animals, 5-week-old ICR male mice were used, and as chemical stimulants, PBQ (phenyl-p-quinone, 0.02%) was used. 20 mg of the test substance was suspended in 10 mL of physiological saline per kg body weight of the mouse. One hour before the administration of PBQ, the test substance and the carrier were orally administered, and PBQ was injected intraperitoneally in a volume of 10 mL / kg body weight. The number of kinks of each individual for each test group was measured at 10 minute intervals from 5 minutes after injection. The analgesic efficacy of the test substance was confirmed by the inhibitory power (%) calculated as a decrease in the number of times compared to the control group.
Inhibitory power (%) = (carrier-only administration control−test substance administration group) / (carrier-only administration control) × 100

Experimental Example 4 Toxicity experiments To investigate the toxicity of newly produced compounds, mice were used for acute oral toxicity studies.

  ICR male mice were divided into 4 groups of 10 mice per group, and the compound 2- [4- (3-chloropyridin-2-yl) -phenyl] -6-trifluoromethyl-1H-benzimidazole (1 ), 6-tert-butyl-2- [4- (3-chloropyridin-2-yl) phenyl] -1H-benzimidazole (3), N- [4 ′-(4,6-bistrifluoromethyl-1H) -Benzimidazol-2-yl) -3-fluorobiphenyl-4-yl] methanesulfonamide (29), 4-bromo-6- (trifluoromethyl) -2- (4- (3- (trifluoromethyl) Pyridin-2-yl) phenyl) -1H-benzimidazole (36), 6-tert-butyl-2- [4- (3-chloropyridin-2-yl) naphthalen-1-yl] -1 -Benzimidazole (105), 3-trifluoromethyl-6 '-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3'] bipyridine (158), 6-bromo-2 ( 5- (3- (trifluoromethyl) pyridin-2-yl) pyridin-2-yl) -1H-benzimidazole (165) and 6 ′-(6-morpholin-4-yl-1H-benzimidazol-2- Yl) -3-trifluoromethyl- [2,3 ′] bipyridine (169) was orally administered at a dose of 0 mg / kg for the control and 125, 250, 500 mg / kg for the test group, respectively, and then for 14 days. The presence or absence of toxicity was observed by mortality, clinical symptoms, weight changes, and microscopic diagnosis.

  As a result of the test, none of the mice to which the target compound was administered died, and no symptoms different from the control group were found in clinical symptoms, body weight changes, microscopic diagnosis, and the like. Therefore, it was confirmed that the compound of the present invention is a safe drug.

  As described above, the compound of the present invention is pain, acute pain, chronic pain, neuropathic pain, postoperative pain, migraine, joint pain, neuropathy, nerve damage, diabetic neuropathy, neuropathic disease, Nervous dermatitis, stroke, bladder hypersensitivity, irritable bowel syndrome, respiratory diseases such as asthma, chronic obstructive pulmonary disease, burns, psoriasis, pruritus, vomiting, skin, eye and mucous membrane irritation It is useful for prevention and treatment of duodenal ulcer, inflammatory bowel disease and inflammatory disease.

  While preferred embodiments of the invention have been disclosed for purposes of illustration, those skilled in the art will recognize that various modifications, additions and substitutions can be made without departing from the scope and spirit of the invention as disclosed in the appended claims. It should be understood that this can be done.

Claims (4)

A compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof .

(In the above formula,
R ¹ is selected from the group consisting of a pyridine, pyrimidine, pyrazole, pyrazine, phenyl, naphthalene, pyridazine, or pyrrole group, wherein the cyclic group is substituted or unsubstituted with one or more R ^a A cyclic group;
Each R ^a is haloalkyl having a carbon number of 1-6; alkyl sulfonamide mono- or di-substituted or 1 to 6 carbon atoms; halogen atoms; cyano from the group consisting of, independently selected;
A is CO ;
n is an integer of 0 or 1;
W is N or CR ³ ;
X is N or CR ⁴ ;
R ² is hydrogen;
R ³ and R ⁴ may be the same or different and each independently represents hydrogen; or a halogen atom; or R ³ and R ⁴ together form a saturated 5, 6 or 7 membered monocycle. Forming;
Q ¹ is N or CR ⁶ ;
Q ² is CR ⁷ ;
Q ³ is CR ⁸ ;
Q ⁴ is CR ⁹ ;
R ⁶ , R ⁷ , R ⁸ and R ⁹ may be the same or different and are each independently hydrogen ; tert-butyl ; alkoxy having 1 to 8 carbons; haloalkyl having 1 to 6 carbons; halogen atom Amino mono- or di-substituted with alkyl having 1 to 6 carbons; morpholine; thiomorpholine; or pyrrolidine;
However, the following compounds are excluded from Chemical Formula 1:

) 2 - [4- (3-chloro-2-yl) phenyl] -6-trifluoromethyl -1H- benzimidazole,
6-chloro-2- [4- (3-chloropyridin-2-yl) phenyl] -1H-benzimidazole,
6-tert-butyl-2- [4- (3-chloropyridin-2-yl) phenyl] -1H-benzimidazole,
2- [4- (3-chloropyridin-2-yl) phenyl] -6-fluoro-1H-benzimidazole,
2- [4- (3-chloropyridin-2-yl) phenyl] -6-methoxy-1H-benzimidazole,
4-chloro-2- [4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
2- [4- (3-chloropyridin-2-yl) phenyl] -4,6-bistrifluoromethyl-1H-benzimidazole,
2- [4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-imidazo [4,5-b] pyridine,
2- [4- (3-chloropyridin-2-yl) phenyl] -3H-imidazo [4,5-b] pyridine,
2- [4- (3-chloropyridin-2-yl) phenyl] -6,7-dimethyl-1H-benzimidazole,
2- [4- (3-chloropyridin-2-yl) phenyl] -1H-benzimidazole,
2- [4- (3-chloropyridin-2-yl) phenyl] -5,6-dichloro-1H-benzimidazole,
6-bromo-2- (4- (3-chloropyridin-2-yl) phenyl) -1H-benzimidazole,
4-bromo-2- (4- (3-chloropyridin-2-yl) phenyl) -6- (trifluoromethyl) -1H-benzimidazole,
6-bromo-2- (4- (3-chloropyridin-2-yl) phenyl-1H-imidazo [4,5-b] pyridine,
4,6-dibromo-2- [4- (3-chloropyridin-2-yl) phenyl] -1H-benzimidazole,
2- [4- (3-chloropyridin-2-yl) phenyl] -6-morpholin-4-yl-1H-benzimidazole,
2- [4- (3-chloropyridin-2-yl) phenyl] -6-thiomorpholin-4-yl-1H-benzimidazole,
2- [4- (3-chloropyridin-2-yl) phenyl] -4-morpholin-4-yl-6-trifluoromethyl-1H-benzimidazole,
2- [4- (3-chloropyridin-2-yl) phenyl] -4-thiomorpholin-4-yl-6-trifluoromethyl-1H-benzimidazole,
2- [4- (3-chloropyridin-2-yl) phenyl] -4-pyrrolidin-1-yl-6-trifluoromethyl-1H-benzimidazole,
{2- [4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazol-4-yl} diethylamine,
2- [4- (3-chloropyridin-2-yl) phenyl] -6-morpholin-4-yl-1H-imidazo [4,5-b] pyridine,
2- [4- (3-chloropyridin-2-yl) phenyl] -6-pyrrolidin-1-yl-1H-imidazo [4,5-b] pyridine,
6-tert-butyl-2- [4- (3,5-dichloropyridin-2-yl) phenyl] -1H-benzimidazole,
2- [4- (3,5-dichloropyridin-2-yl) phenyl] -4,6-bistrifluoromethyl-1H-benzimidazole,
6-tert-butyl-2- [4- (3-chloro-5-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
2- [4- (3-chloro-5-trifluoromethylpyridin-2-yl) phenyl] -4,6-bistrifluoromethyl-1H-benzimidazole,
2- [4- (3-chloro-5-trifluoromethylpyridin-2-yl) phenyl] -5,7-bistrifluoromethyl-1H-benzimidazole,
N- [4 ′-(4,6-bistrifluoromethyl-1H-benzimidazol-2-yl) -3-fluorobiphenyl-4-yl] methanesulfonamide,
6-tert-butyl-2- [4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
4-chloro-6-trifluoromethyl-2- [4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
6-chloro-2- [4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
4,6-bistrifluoromethyl-2- [4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
6-trifluoromethyl-2- [4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-imidazo [4,5-b] pyridine,
5,6-dichloro-2- [4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
4-bromo-6- (trifluoromethyl) -2- (4- (3- (trifluoromethyl) pyridin-2-yl) phenyl) -1H-benzimidazole,
6-bromo-2- (4- (3- (trifluoromethyl) pyridin-2-yl) phenyl) -1H-benzimidazole,
6-fluoro-2- (4- (3- (trifluoromethyl) pyridin-2-yl) phenyl) -1H-benzimidazole,
6-bromo-2- (4- (3- (trifluoromethyl) pyridin-2-yl) phenyl-1H-imidazo [4,5-b] pyridine,
4,6-dibromo-2- [4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
6-morpholin-4-yl-2- [4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
6-thiomorpholin-4-yl-2- [4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
Diethyl- {2- [4- (3-trifluoromethylpyridin-2-yl) phenyl] -3H-benzimidazo-5-yl} amine,
4-morpholin-4-yl-6-trifluoromethyl-2- [4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
4-thiomorpholin-4-yl-6-trifluoromethyl-2- [4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
4-pyrrolidin-1-yl-6-trifluoromethyl-2- [4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
6-tert-butyl-2- (4-pyridin-2-ylphenyl) -1H-benzimidazole,
6- (trifluoromethyl) -2- (4- (pyridin-2-yl) phenyl) -1H-benzimidazole,
4-chloro-6- (trifluoromethyl) -2- (4- (pyridin-2-yl) phenyl) -1H-benzimidazole,
5,6-dichloro-2- (4- (pyridin-2-yl) phenyl) -1H-benzimidazole,
4,6-bis (trifluoromethyl) -2- (4- (pyridin-2-yl) phenyl) -1H-benzimidazole,
6-fluoro-2- (4- (pyridin-2-yl) phenyl) -1H-benzimidazole,
6-bromo-2- (4- (pyridin-2-yl) phenyl) -1H-imidazo [4,5-b] pyridine,
4,6-dibromo-2- (4-pyridin-2-ylphenyl) -1H-benzimidazole,
2- [4- (6-chloro-5-methylpyridazin-3-yl) phenyl] -4,6-bistrifluoromethyl-1H-benzimidazole,
2- [4- (6-chloro-5-methylpyridazin-3-yl) phenyl] -5,7-bistrifluoromethyl-1H-benzimidazole,
4-bromo-6- (trifluoromethyl) -2- (4- (4- (trifluoromethyl) pyrimidin-2-yl) phenyl) -1H-benzimidazole,
4,6-dibromo-2- [4- (4-trifluoromethylpyrimidin-2-yl) phenyl] -1H-benzimidazole,
6-tert-butyl-2- (4- (pyrimidin-2-yl) phenyl) -1H-benzimidazole,
2- (4- (6- (trifluoromethyl) -1H-benzimidazol-2-yl) phenyl) pyridine-3-carbonitrile,
2- (4- (6- (tert-butyl-1H-benzimidazol-2-yl) phenyl) pyridine-3-carbonitrile,
6 ′-(4,6-dibromo-1H-benzimidazol-2-yl)-[2,3 ′] bipyridyl-3-carbonitrile,
2- [4- (3-chloropyrazin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
6-tert-butyl-2- [4- (3-chloropyrazin-2-yl) phenyl] -1H-benzimidazole,
6-bromo-2- [4- (3-chloropyrazin-2-yl) phenyl] -1H-benzimidazole,
5,6-dichloro-2- [4- (3-chloropyrazin-2-yl) phenyl] -1H-benzimidazole,
6-bromo-2- [4- (3-chloropyrazin-2-yl) phenyl] -1H-imidazo [4,5-b] pyridine,
6-tert-butyl-2- [4- (3-chloropyridin-2-yl) -2-fluorophenyl] -1H-benzimidazole,
4-chloro-2- [4- (3-chloropyridin-2-yl) -2-fluorophenyl] -6-trifluoromethyl-1H-benzimidazole,
2- [4- (3-chloropyridin-2-yl) -2-fluorophenyl] -6-methoxy-1H-benzimidazole,
6-tert-butyl-2- [4- (3,5-dichloropyridin-2-yl) -2-fluorophenyl] -1H-benzimidazole,
4-chloro-2- [4- (3,5-dichloropyridin-2-yl) -2-fluorophenyl] -6-trifluoromethyl-1H-benzimidazole,
2- [4- (3,5-dichloropyridin-2-yl) -2-fluorophenyl] -4,6-bistrifluoromethyl-1H-benzimidazole,
4-chloro-2- [4- (3-chloro-5-trifluoromethylpyridin-2-yl) -2-fluorophenyl] -6-trifluoromethyl-1H-benzimidazole,
2- [4- (3-chloro-5-trifluoromethylpyridin-2-yl) -2-fluorophenyl] -6-trifluoromethyl-1H-imidazo [4,5-b] pyridine,
2- [4- (3-chloro-5-trifluoromethylpyridin-2-yl) -2-fluorophenyl] -6-methoxy-1H-benzimidazole,
N- [3,3′-difluoro-4 ′-(6-methoxy-1H-benzimidazol-2-yl) biphenyl-4-yl] methanesulfonamide,
2- [2-fluoro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
6-tert-butyl-2- [2-fluoro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
6-chloro-2- [2-fluoro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
5-chloro-2- [2-fluoro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
4-chloro-2- [2-fluoro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
7-chloro-2- [2-fluoro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -5-trifluoromethyl-1H-benzimidazole,
2- (2-fluoro-4-pyridin-2-yl) phenyl-6-trifluoromethyl-1H-benzimidazole,
6-tert-butyl-2- (2-fluoro-4-pyridin-2-yl) phenyl-1H-benzimidazole,
6-chloro-2- (2-fluoro-4-pyridin-2-yl) phenyl-1H-benzimidazole,
2- (2-fluoro-4-pyridin-2-yl) phenyl-4,6-bistrifluoromethyl-1H-benzimidazole,
2- [2-chloro-4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
4-chloro-2- [2-chloro-4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
2- [2-chloro-4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-imidazo [4,5-b] pyridine,
2- [2-chloro-4- (3,5-dichloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
4-chloro-2- [2-chloro-4- (3,5-dichloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
2- [2-chloro-4- (3,5-dichloropyridin-2-yl) phenyl] -4,6-bistrifluoromethyl-1H-benzimidazole,
2- [2-chloro-4- (3,5-dichloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-imidazo [4,5-b] pyridine,
2- [2-chloro-4- (3-chloro-5-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
4-chloro-2- [2-chloro-4- (3-chloro-5-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
N- [4 ′-(6-tert-butyl-1H-benzimidazol-2-yl) -3′-chloro-3-fluorobiphenyl-4-yl] methanesulfonamide,
N- [3′-chloro-4 ′-(4-chloro-6-trifluoromethyl-1H-benzimidazol-2-yl) -3-fluorobiphenyl-4-yl] methanesulfonamide,
N- [4 ′-(4,6-bistrifluoromethyl-1H-benzimidazol-2-yl) -3′-chloro-3-fluorobiphenyl-4-yl] methanesulfonamide,
2- [2-chloro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
4-chloro-2- [2-chloro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
2- [2-chloro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -4,6-bistrifluoromethyl-1H-benzimidazole,
6-tert-butyl-2- [2-chloro-4- (3-methylpyridin-2-yl) phenyl] -1H-benzimidazole,
6-chloro-2- (2-chloro-4-pyridin-2-ylphenyl) -1H-benzimidazole,
2- (2-chloro-4-pyridin-2-ylphenyl) -6-trifluoromethyl-1H-imidazo [4,5-b] pyridine,
2- (2-chloro-4-pyridin-2-ylphenyl) -6-methoxy-1H-benzimidazole,
2- [4- (3-chloropyridin-2-yl) naphthalen-1-yl] -6-trifluoromethyl-1H-benzimidazole,
6-tert-butyl-2- [4- (3-chloropyridin-2-yl) naphthalen-1-yl] -1H-benzimidazole,
2- [4- (3-chloropyridin-2-yl) naphthalen-1-yl] -4,6-bistrifluoromethyl-1H-benzimidazole,
2- [4- (3-chloropyridin-2-yl) naphthalen-1-yl] -6-trifluoromethyl-1H-imidazo [4,5-b] pyridine,
6-tert-butyl-2- [4- (3,5-dichloropyridin-2-yl) naphthalen-1-yl] -1H-benzimidazole,
2- [4- (3,5-dichloropyridin-2-yl) naphthalen-1-yl] -4,6-bistrifluoromethyl-1H-benzimidazole,
6-tert-butyl-2- [4- (3-chloro-5-trifluoromethylpyridin-2-yl) naphthalen-1-yl] -1H-benzimidazole,
2- [4- (3-chloro-5-trifluoromethylpyridin-2-yl) naphthalen-1-yl] -4,6-bistrifluoromethyl-1H-benzimidazole,
N- {4- [4- (4,6-bistrifluoromethyl-1H-benzimidazol-2-yl) naphthalen-1-yl] -2-fluorophenyl} methanesulfonamide,
6-trifluoromethyl-2- [4- (3-trifluoromethylpyridin-2-yl) naphthalen-1-yl] -1H-benzimidazole,
6-tert-butyl-2- (4-pyridin-2-ylnaphthalen-1-yl) -1H-benzimidazole,
2- (4-pyridin-2-ylnaphthalen-1-yl) -4,6-bistrifluoromethyl-1H-benzimidazole,
6-tert-butyl-2- [3-chloro-4- (3-chloropyridin-2-yl) phenyl] -1H-benzimidazole,
2- [3-chloro-4- (3,5-dichloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
6-tert-butyl-2- [3-chloro-4- (3,5-dichloropyridin-2-yl) phenyl] -1H-benzimidazole,
2- [3-chloro-4- (3,5-dichloropyridin-2-yl) phenyl] -6-methoxy-1H-benzimidazole,
2- [3-chloro-4- (3,5-dichloropyridin-2-yl) phenyl] -5-methoxy-1H-benzimidazole,
2- [3-chloro-4- (3-chloro-5-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
6-tert-butyl-2- [3-chloro-4- (3-chloro-5-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
2- [3-chloro-4- (3-chloro-5-trifluoromethylpyridin-2-yl) phenyl] -6-methoxy-1H-benzimidazole,
2- [3-chloro-4- (3-chloro-5-trifluoromethylpyridin-2-yl) phenyl] -5-methoxy-1H-benzimidazole,
N- [2′-chloro-4 ′-(4-chloro-6-trifluoromethyl-1H-benzimidazol-2-yl) -3-fluorobiphenyl-4-yl] methanesulfonamide,
N- [4 ′-(4,6-bistrifluoromethyl-1H-benzimidazol-2-yl) -2′-chloro-3-fluorobiphenyl-4-yl] methanesulfonamide,
2- (3-chloro-4-pyridin-2-ylphenyl) -6-trifluoromethyl-1H-benzimidazole,
6-tert-butyl-2- (3-chloro-4-pyridin-2-ylphenyl) -1H-benzimidazole,
6-chloro-2- (3-chloro-4-pyridin-2-ylphenyl) -1H-benzimidazole,
4-chloro-2- (3-chloro-4-pyridin-2-ylphenyl) -6-trifluoromethyl-1H-benzimidazole,
5,6-dichloro-2- (3-chloro-4- (pyridin-2-yl) phenyl) -1H-benzimidazole,
6-bromo-2- (3-chloro-4- (pyridin-2-yl) phenyl) -1H-benzimidazole,
2- [3-chloro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
6-tert-butyl-2- [3-chloro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
6-chloro-2- [3-chloro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -1H-benzimidazole,
2- [3-chloro-4- (3-trifluoromethylpyridin-2-yl) phenyl] -6-methoxy-1H-benzimidazole,
2- [3-chloro-4- (3-methylpyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
3-chloro-6 ′-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine,
3-chloro-6 ′-(6-chloro-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine,
3-chloro-6 ′-(4-chloro-6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine,
6 ′-(4,6-bistrifluoromethyl-1H-benzimidazol-2-yl) -3-chloro- [2,3 ′] bipyridine,
4-bromo-2- (5- (3-chloropyridin-2-yl) pyridin-2-yl) -6- (trifluoromethyl) -1H-benzimidazole,
6-bromo-2- (5- (3-chloropyridin-2-yl) pyridin-2-yl) -1H-benzimidazole,
6 ′-(6-tert-butyl-1H-benzimidazol-2-yl) -3-chloro- [2,3 ′] bipyridine,
3-chloro-6 ′-(5,6-dichloro-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine,
3-chloro-6 ′-(4,6-dibromo-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine,
6 ′-(6-bromo-1H-imidazo [4,5-b] pyridin-2-yl) -3-chloro- [2,3 ′] bipyridine,
3-chloro-6 ′-(6-morpholin-4-yl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine,
3-chloro-6 ′-(6-thiomorpholin-4-yl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine,
3-chloro-6 ′-(4-morpholin-4-yl-6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine,
3-chloro-6 ′-(4-thiomorpholin-4-yl-6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine,
3-chloro-6 ′-(4-pyrrolidin-1-yl-6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine,
3,5-dichloro-6 ′-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine,
6 ′-(6-tert-butyl-1H-benzimidazol-2-yl) -3,5-dichloro- [2,3 ′] bipyridine,
3,5-dichloro-6 ′-(6-chloro-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine,
3,5-dichloro-6 ′-(4-chloro-6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine,
6 ′-(4,6-bistrifluoromethyl-1H-benzimidazol-2-yl) -3,5-dichloro- [2,3 ′] bipyridine,
6 ′-(4,6-bistrifluoromethyl-1H-benzimidazol-2-yl) -3-chloro-5-trifluoromethyl- [2,3 ′] bipyridine,
6 ′-(6-methoxy-1H-benzimidazol-2-yl) -3-chloro-5-trifluoromethyl- [2,3 ′] bipyridine,
3-trifluoromethyl-6 ′-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine,
6 ′-(6-tert-butyl-1H-benzimidazol-2-yl) -3-trifluoromethyl- [2,3 ′] bipyridine,
6 ′-(6-chloro-1H-benzimidazol-2-yl) -3-trifluoromethyl- [2,3 ′] bipyridine,
6 ′-(4-chloro-6-trifluoromethyl-1H-benzimidazol-2-yl) -3-trifluoromethyl- [2,3 ′] bipyridine,
6 ′-(5-trifluoromethyl-7-chloro-1H-benzimidazol-2-yl) -3-trifluoromethyl- [2,3 ′] bipyridine,
6 ′-(4,6-bistrifluoromethyl-1H-benzimidazol-2-yl) -3-trifluoromethyl- [2,3 ′] bipyridine,
6 ′-(5,6-dichloro-1H-benzimidazol-2-yl) -3-trifluoromethyl- [2,3 ′] bipyridine,
4-bromo-6- (trifluoromethyl) -2- (5- (3- (trifluoromethyl) pyridin-2-yl) pyridin-2-yl) -1H-benzimidazole,
6-bromo-2- (5- (3- (trifluoromethyl) pyridin-2-yl) pyridin-2-yl) -1H-benzimidazole,
6-fluoro-2- (5- (3- (trifluoromethyl) pyridin-2-yl) pyridin-2-yl) -1H-benzimidazole,
6 ′-(6-bromo-1H-imidazo [4,5-b] pyridin-2-yl) -3-trifluoromethyl [2,3 ′] bipyridine,
6 ′-(4,6-dibromo-1H-benzimidazol-2-yl) -3-trifluoromethyl- [2,3 ′] bipyridine,
6 ′-(6-morpholin-4-yl-1H-benzimidazol-2-yl) -3-trifluoromethyl- [2,3 ′] bipyridine,
6 ′-(4-morpholin-4-yl-6-trifluoromethyl-1H-benzimidazol-2-yl) -3-trifluoromethyl- [2,3 ′] bipyridine,
6 ′-(6-chloro-1H-benzoimidazol-2-yl)-[2,3 ′] bipyridine,
6 ′-(6-trifluoromethyl-1H-imidazo [4,5-b] pyridin-2-yl)-[2,3 ′] bipyridine,
5,6-dichloro-2- (5- (pyridin-2-yl) pyridin-2-yl) -1H-benzimidazole,
6-tert-butyl-2- (6-naphthalen-1-ylpyridin-3-yl) -1H-benzimidazole,
2- (6-naphthalen-1-ylpyridin-3-yl) -4,6-bistrifluoromethyl-1H-benzimidazole,
2- (6-naphthalen-1-ylpyridin-3-yl) -5,7-bistrifluoromethyl-1H-benzimidazole,
6- (trifluoromethyl) -2- (6- (naphthalen-1-yl) pyridin-3-yl) -1H-benzimidazole,
6-chloro-2- (6- (naphthalen-1-yl) pyridin-3-yl) -1H-benzimidazole,
2- (4-pyrrol-1-ylphenyl) -6-trifluoromethyl-1H-benzimidazole,
2- (4-pyrrol-1-ylphenyl) -3H-imidazo [4,5-b] pyridine,
6-chloro-2- (4-pyrrol-1-ylphenyl) -1H-benzimidazole,
6-tert-butyl-2- (4-pyrrol-1-ylphenyl) -1H-benzimidazole,
6-fluoro-2- (4-pyrrol-1-ylphenyl) -1H-benzimidazole,
2-biphenyl-4-yl-6-trifluoromethyl-1H-benzimidazole,
2-biphenyl-4-yl-3H-imidazo [4,5-b] pyridine,
2-biphenyl-4-yl-6-chloro-1H-benzimidazole,
2-biphenyl-4-yl-6-tert-butyl-1H-benzimidazole,
2-biphenyl-4-yl-6-fluoro-1H-benzimidazole,
2-biphenyl-4-yl-6-methoxy-1H-benzimidazole,
2- (4-phenoxyphenyl-6-trifluoromethyl) -1H-benzimidazole,
2- (4-phenoxyphenyl) -3H-imidazo [4,5-b] pyridine,
6-chloro-2- (4-phenoxyphenyl) -1H-benzimidazole,
6-tert-butyl-2- (4-phenoxyphenyl) -1H-benzimidazole,
6-fluoro-2- (4-phenoxyphenyl) -1H-benzimidazole,
6-methoxy-2- (4-phenoxyphenyl) -1H-benzimidazole,
2- [3- (4-chloropyrazol-1-ylmethyl) phenyl] -6-trifluoromethyl-1H-benzimidazole,
6-chloro-2- [3- (4-chloropyrazol-1-ylmethyl) phenyl] -1H-benzimidazole,
6-tert-butyl-2- [3- (4-chloropyrazol-1-ylmethyl) phenyl] -1H-benzimidazole,
2- [3- (4-chloropyrazol-1-ylmethyl) phenyl] -6-fluoro-1H-benzimidazole,
Phenyl- [4- (6-trifluoromethyl-1H-benzimidazol-2-yl) phenyl] methanone,
[4- (6-tert-butyl-1H-benzimidazol-2-yl) phenyl] phenylmethanone,
2- [4- (3-chloropyridin-2-yl) phenyl] -6-trifluoromethyl-1H-benzimidazole hydrochloride,
6-tert-butyl-2- [4- (3-chloropyridin-2-yl) phenyl] -1H-benzimidazole hydrochloride,
6-tert-butyl-2- [4- (3-chloropyridin-2-yl) naphthalen-1-yl] -1H-benzimidazole hydrochloride,
6 ′-(4,6-bistrifluoromethyl-1H-benzimidazol-2-yl) -3-chloro [2,3 ′] bipyridine hydrochloride,
3-trifluoromethyl-6 ′-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine hydrochloride,
6-tert-butyl-2- [4- (3-chloropyridin-2-yl) phenyl] -1H-benzimidazole sodium salt,
3-trifluoromethyl-6 ′-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine sulfate,
3-trifluoromethyl-6 ′-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridine phosphate,
3-trifluoromethyl-6 ′-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridinemethanesulfonate,
3-trifluoromethyl-6 ′-(6-trifluoromethyl-1H-benzimidazol-2-yl)-[2,3 ′] bipyridinebenzenesulfonate,
A compound or a pharmaceutically acceptable salt thereof , which is selected from the group consisting of: A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient. Pain, acute pain, chronic pain, neuropathic pain, surgery, comprising a pharmaceutically acceptable carrier and the compound of claim 1 or 2 as an active ingredient, or a pharmaceutically acceptable salt thereof. Post-pain, migraine, joint pain, neuropathy, nerve damage, diabetic neuropathy, neuropathic disease, neurodermatitis, stroke, bladder hypersensitivity, irritable bowel syndrome, respiratory disease, asthma, chronic obstructive Prevention of diseases selected from the group consisting of lung disease, burns, psoriasis, pruritus, vomiting, irritation of skin, eyes and mucous membranes, gastric / duodenal ulcer, inflammatory bowel disease, inflammatory diseases and combinations thereof Or a therapeutic pharmaceutical composition.